Transferable model for the atomistic simulation of Al2O3.
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Journal Article↗
Biomedical subjects
M Exner
Publications and source records attributed to M Exner.
Receptor-associated protein and members of the low density lipoprotein receptor family share a common epitope. An extended model for the development of passive Heymann nephritis.
Heymann nephritis is an experimental rat model for human membranous glomerulonephritis. Two target antigens have been identified in the proximal tubule brush border of rat kidneys. One of them is megalin, a 600-kDa membrane protein that belongs to the family of low density lipoprotein receptor (LDLR)-related proteins. The other one is receptor-associated protein (RAP), a polypeptide of 40 kDa that associates with members of the LDLR family. Here we show that antibodies produced against recombinant human RAP strongly cross-react with the chicken oocyte receptor for very low density lipoprotein and vitellogenin (LR8), and with two other members of the LDLR family, LDLR-related protein and megalin. The interaction of this antibody with LR8 showed binding characteristics exactly as those demonstrated for the physiological ligands of this receptor, in that binding of the antibody: (i) is Ca2+-dependent; (ii) is abolished by unfolding of the cysteine-rich binding domain by reduction; and (iii) interferes with the binding of very low density lipoprotein and vitellogenin. Immunopurification of the LR8-specific subpopulation of the polyclonal antiserum yielded an IgG fraction strongly reacting with LR8 as well as with RAP. Using recombinant fragments of RAP and peptide mapping, the cross-reacting epitope(s) could be narrowed down to three short sequences (5-7 residues) in the COOH-terminal part of the protein. After immunization with RAP, anti-LR8 antibodies and anti-RAP antibodies arise simultaneously, indicating that the receptor-specific activity is not due to anti-idiotypic antibodies. These findings suggest the existence of a common epitope(s) on RAP and members of the LDL receptor family. Based on these results, we present an extended molecular model for the development of passive Heymann nephritis.
Animals↗
Creatine kinase-mb fraction and cardiac troponin T to diagnose acute myocardial infarction after cardiopulmonary resuscitation.
OBJECTIVES: This study sought to evaluate the diagnostic value of the biochemical markers creatine kinase (CK), creatine kinase-MB fraction (CK-MB) and cardiac troponin T (cTNT) to diagnose acute myocardial infarction (AMI) after cardiopulmonary resuscitation (CPR). BACKGROUND: Elevations of CK and CK-MB after CPR are a frequent finding and might be associated with ischemic myocardial injury, as well as physical trauma to the chest. METHODS: Patients who had cardiac arrest and primary successful resuscitation were included in the study. The diagnosis of AMI was confirmed or ruled out by means of typical electrocardiographic findings, thallium-201 myocardial scintigraphy or autopsy, if death occurred during the hospital period, in 39 primary survivors of sudden cardiac death. In 24 patients (62%) the diagnosis of AMI was established. Serum cTNT, CK and CK-MB were measured, and the CK-MB/CK ratio was calculated on admission and after 12 h. RESULTS: On admission all markers of myocardial injury proved to be weak methods for the diagnosis of AMI. After 12 h cTNT as well as CK-MB exhibited a similar diagnostic performance; CK and the CK-MB/CK ratio proved to be worthless. Sensitivity and specificity for a cTNT cutoff value of 0.6 ng/ml, 12 h after cardiac arrest, were 96% and 80%, respectively. For a CK-MB cutoff value of 26 U/liter, sensitivity was 96% and specificity was 73%. CONCLUSIONS: Cardiac TNT and CK-MB are valuable tools in detecting AMI as the cause of sudden cardiac death. However, there is a considerable lack of sensitivity and specificity. Cardiac injury is probably caused not only by AMI, but also by myocardial damage related to CPR efforts.
Animals↗
Induction of passive Heymann nephritis with antibodies specific for a synthetic peptide derived from the receptor-associated protein.
Passive Heymann nephritis (pHN) is an experimental rat model for human membranous glomerulopathy. In pHN, the formation of subepithelial immune deposits (ID) involves as antigenic targets the membrane glycoprotein gp330/megalin and the 44-kD receptor-associated protein (RAP). A single binding site for ID- inducing antibodies (Abs) was previously mapped to the 86 NH2-terminal amino acids of RAP (RAP1-86). To further narrow this epitope, Abs eluted from the glomeruli were immunoblotted on membranes that were loaded with overlapping synthetic peptides representing the amino acid sequence of RAP (SPOTs system). Two adjacent Ab-binding domains with the sequences PVRLAF, (amino acids 39-44) and HSD-LKIQE (amino acids 46-53), which were separated by a single L residue at amino acid 45, were detected. Rabbit Abs raised against synthetic peptides containing these domains individually (P31-44 and P46-53) failed to procedure glomerular IDs. By contrast, Abs raised against a larger composite peptide (P31-53) induced IDs within 3d that were firmly cross linked to the glomerular basement membrane. These data suggest that Ab binding in vivo depends on the conformation of the antigenic target sequence that is preserved in the synthetic peptide P31-53, which covers the entire Ab-binding domain of RAP but not in its subdomains, P31-44 and P46-53. Collectively, these results locate the sole ID-inducing epitope of RAP to amino acids 39-53.
Amino Acid Sequence↗
Use of immobilized synthetic peptides for the identification of contact sites between human interleukin-6 and its receptor.
Synthetic peptides immobilized on cellulose membranes proved to be a powerful tool for the identification of sites in the cytokine IL-6 involved in receptor binding. Similarly, a region in the extracellular part of the IL-6 receptor which is important for interaction with its ligand was identified.
Amino Acid Sequence↗
Elevated levels of soluble CD14 in serum of patients with acute Plasmodium falciparum malaria.
Serum sCD14, tumour necrosis factor-alpha (TNF-alpha), IL-6, and endotoxin were analysed in 45 patients with complicated malaria, in 14 patients with Gram-negative septicaemia and in 24 healthy subjects by ELISA. Malaria patients with renal failure (n = 16) had higher levels than patients without renal failure (n = 29) (8116 + 1440 micrograms/l versus 9453 + 1017 micrograms/l; P < 0.05) and both had higher levels than patients with septicaemia (6155 + 1635 micrograms/l) and normal subjects (2776 + 747 micrograms/l). A significant correlation between sCD14 and IL-6 (r = 0.756) and TNF (r = 0.822) existed. However, no relation between sCD14 and serum endotoxin or indices of clinical disease severity (parasitaemia, fever, parasite or fever clearance time) was seen. Although the role of sCD14 in malaria remains to be determined, elevated levels may participate in the inflammatory response in complicated malaria.
Acute Disease↗
Detection of anti-neutrophil cytoplasmic antibodies after acute Plasmodium falciparum malaria.
Four of 30 patients with Plasmodium falciparum infection in Bangkok, Thailand, were positive for anti-neutrophil cytoplasmic antibodies by indirect immunofluorescence 1 month after antimalarial therapy. No myeloperoxidase, proteinase 3, lactoferrin, or elastase reactivity was found. Since no evidence of vasculitis was seen in these patients, anti-neutrophil cytoplasmic antibody production in malaria-infected susceptible patients probably represents a secondary response, indicating neutrophil activation.
Acute Disease↗
[Transmission of pathogenic human viruses by foods: hepatitis A epidemic caused by baked goods in the Euskirchen district)].
In the last few years many reports have documented that human pathogenic viruses are transmitted via food and can cause epidemics. Between November 1994 and February 1995 a HAV epidemic was recorded in the village and agricultural area of Euskirchen (Germany). 49 persons with HAV infections were registered. It seems that the epidemic started in a bakery and was caused by an employee who had spent his holidays in the Dominican Republic and came back already excreting the virus via his faeces. Two weeks later he developed a symptomatic illness. HAV is transmitted via a fecal-oral cycle. Lack of hygiene in food production and distribution cause the risk of secondary virus contamination. Virus transmission via food is first of all a problem in uncooked food. To ensure success in food safety in respect of foodborne human pathogenic viruses it is important to establish personal hygienic education, cleaning and disinfection plans and preventive measures such as immunization to avoid viruses in the food.
Disease Outbreaks↗
Lipoproteins accumulate in immune deposits and are modified by lipid peroxidation in passive Heymann nephritis.
Proteinuria in passive Heymann nephritis is primarily caused by reactive oxygen species that are produced by glomerular cells. Reactive oxygen species apparently exert their damaging effects on the glomerular filter by lipid peroxidation and subsequent adduct formation on matrix proteins of glomerular basement membranes. This raised the question as to the source of polyunsaturated fatty acids required as substrates for lipid peroxidation. Here we have localized by immunocytochemistry rat apolipoprotein E and apolipoprotein B within subepithelial immune deposits. Moreover, apolipoprotein B extracted from isolated glomeruli of proteinuric passive Heymann nephritis rats shows degradation and lipid peroxidation adduct formation, similar to apoproteins of oxidized lipoproteins in atherosclerotic lesions. These data provide evidence that lipoproteins accumulate within immune deposits and suggest that their lipids generate lipid-peroxidation-derived reactive compounds.
Animals↗
[Risk assessment and risk prevention in infectious diseases].
The purpose of risk assessment is to provide source data to state and local health agencies and other administrative departments to aid in the development of approaches for risk management and preventive strategies. In respect of the far reaching consequences it is necessary to have evaluated and accepted measures for the risk assessment. The system of risk assessment was developed in the USA for the assessment of chemical substances and includes the identification of the hazard, the exposure assessment, the dose-response-assessment and the risk assessment. Basis for the risk assessment are detailed information of the chemical substance or the pathogen and epidemiologic data. Preventive strategies and risk management like the stop of production have great social and economic consequences. Risk management must be highly effective. In a historic review it is described that in the past of the former centuries infectious diseases were tried to prevent or control in a wrong manner in consequence of the lack of knowledge about the etiology of infectious diseases. Since Robert Koch there was the beginning of an effective risk assessment and management of infectious diseases. Long time in this century it was thought that infectious diseases wouldn't play any role for the public health. Now it is clear that infectious diseases remain the leading cause of death and disability in the developed and underdeveloped countries and that the risk potential is increasing. Therefore risk-assessment and risk-management developed formerly for chemical substances are necessary for infectious diseases. Specific criteria for-the risk assessment for infectious diseases which are different to chemical substances are discussed like illness related, pathogen related, host related, transmission related factors and general aspects. The most important measures for risk management are discussed.
Communicable Disease Control↗
[Risk of exposure of children to indoor air allergens].
The development of allergic sensitization and disease in children depends mainly upon the genetic predisposition, the time and extent of exposure against allergens and upon environmental factors. Allergen avoidance in infancy substantially lowers the frequency of sensitization and allergic manifestations. In Germany mite allergens are the most important indoor allergens followed by cat allergens and fungal allergens. Private houses bear the greatest risk of exposure to mite allergens. Nevertheless in day nurseries there is a considerable amount of dust samples with mite allergen levels greater than 10 micrograms/g dust (18% of mattresses, 15% of soft toys, pillows etc.). Cat allergen levels in day nurseries and schools are similar to those in houses where a cat has never been kept. There is a correlation between the percentage of children who have cats at home and the cat allergen levels in dust. In an own study the mean numbers of fungal particles in dust samples from day nurseries were higher compared with those from private houses. Higher numbers of fungal particles concerned mostly day nurseries with flat roof and moisture problems. We conclude that generally private houses offer the highest risk of exposure to indoor allergens. In addition public places like day nurseries or schools must be taken into consideration as significant allergen sources.
Air Pollution, Indoor↗
Computer simulation of defects in KTaO3.
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Journal Article↗
Effects of the dopamine autoreceptor antagonist (-)-DS121 on the discriminative stimulus properties of d-amphetamine and cocaine.
(-)-DS121 [S-(-)-3-(3-cyanophenyl)-N-n-propyl piperidine) is a recently synthesised phenylpiperidine derivative suggested to be a dopamine receptor antagonist acting preferentially at dopamine autoreceptors. The drug exerts 'agonist-like' behavioural effects by enhancing dopamine release, but also shares properties in common with neuroleptics. The ability of (-)-DS121 to both generalise to and antagonise the stimulus effects of psychostimulants was determined in rats trained to discriminate d-amphetamine (0.5 mg/kg) or cocaine (5.0 mg/kg) from saline in a two-lever, food-reinforced, drug discrimination task. (-)-DS121 (3.5-14.0 mg/kg) produced small, but significant, increases in drug lever-appropriate responding in both d-amphetamine and cocaine-trained rats. However, there was no indication of a dose-dependent effect in either case. On the other hand, (-)-DS121 dose-dependently reduced response rate. Caffeine produced a higher level of drug lever-appropriate responding than (-)-DS121 in d-amphetamine-trained rats. (-)-DS121 (7.0-14.0 mg/kg) also weakly antagonised the cueing properties of both d-amphetamine and cocaine. A marked response disruption with the drug combination precluded testing of higher doses of (-)-DS121. A combination of subthreshold doses of (-)-DS121 (3.5 mg/kg) and d-amphetamine (0.0625 mg/kg) produced a significant degree of drug lever-appropriate responding, suggesting a synergistic interaction between these drugs. However, such an interaction was not noted with a higher dose of (-)-DS121, or when this drug was administered with a low dose of cocaine (0.25 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
Amphetamine↗
A novel class of autoantigens of anti-neutrophil cytoplasmic antibodies in necrotizing and crescentic glomerulonephritis: the lysosomal membrane glycoprotein h-lamp-2 in neutrophil granulocytes and a related membrane protein in glomerular endothelial cells.
Necrotizing and crescentic glomerulonephritis (NCGN) is frequently associated with circulating antineutrophil cytoplasmic autoantibodies (ANCA). It is established that ANCA are specific for soluble enzymes of granules of polymorphonuclear neutrophil granulocytes (PMN), such as myeloperoxidase (MPO) or protease 3 (PR3). The purpose of this study was to identify membrane proteins of PMNs, and/or glomerular cells, as additional autoantigenic ANCA targets. When membrane protein fractions were prepared from PMNs and isolated human glomeruli, and immunoblotted with ANCA sera of NCGN patients, two bands with apparent molecular masses of 170 and 80-110 kD (gp170/80-110) were labeled in PMNs, and a 130-kD glycoprotein (gp130) in glomeruli. Gp130 was purified, and monoclonal and rabbit antibodies (Abs) were produced which showed the same double specificity as the patient's ANCA. Using these probes, evidence was provided that gp170/80-110 is identical with human lysosomal-associated membrane protein 2 (h-lamp-2), because both proteins were immunologically cross-reactive and screening of a cDNA expression library from human promyelocytic leukemia cells with anti-gp130 Ab yielded a clone derived from h-lamp-2. Gp170/80-110 was localized primarily in granule membranes of resting PMNs, and was translocated to the cell surfaces by activation with FMLP. By contrast, gp130 was localized in the surface membranes of endothelial cells of human glomerular and renal interstitial capillaries, rather than in lysosomes, as found for h-lamp-2. Potential clinical relevance of autoantibodies to gp170/80-110 and gp130 was assessed in a preliminary trial, in which ANCA sera of patients (n = 16) with NCGN were probed with purified or recombinant antigens. Specific reactivity was detected in approximately 90% of cases with active phases of NCGN, and frequently also in combination with autoantibodies specific for PR3 or MPO. Collectively, these data provide evidence that h-lamp-2 in PMNs and a different, structurally related 130-kD membrane protein on the cell surface of renal microvascular endothelial cells are autoantigenic targets for ANCA in patients with active NCGN.
Amino Acid Sequence↗
Dental units: an environmental study of sources of potentially pathogenic mycobacteria.
SETTING: Infections caused by non-tuberculous mycobacteria (NTM) are generally thought to be acquired from environmental sources. However, little is known about the situations in which transmission occurs. OBJECTIVE: In an attempt to identify situations of relevant contact with NTM we investigated the water to which patients are exposed during dental treatment. DESIGN: The concentration and species of NTM were determined in 43 cooling and spray water samples from 21 dental units in ten offices. In addition, mycobacterial colonization of 16 biofilm samples from the waterlines of two dental units was investigated. RESULTS: The mean NTM concentration in the water samples was 365 colony-forming units (cfu) per mL, exceeding the mean drinking water concentration by a factor of almost 400. In the biofilm samples the mean NTM density amounted to 1165 cfu/cm2. The species identified included Mycobacterium gordonae, M. flavescens, M. chelonae, 'M. chelonae-like organism' and M. simiae. CONCLUSION: High numbers of NTM may be swallowed, inhaled or inoculated into oral wounds during dental treatment, possibly resulting in colonization, sensitization or infection. Mycobacterial proliferation in biofilms forming within dental units may explain the extent of NTM contamination of dental spray and cooling water.
Biofilms↗
Functional and regulatory analysis of the OmpF-like porin, OpnP, of the symbiotic bacterium Xenorhabdus nematophilus.
The function and novel regulation of OpnP of the symbiotic/pathogenic bacterium, Xenorhabdus nematophilus was studied. In vitro pore-function analysis of purified OpnP indicated that the single-channel-conductance values were similar to that measured for the porin protein, OmpF, of Esherichia coli. Nucleotide sequence analysis revealed that the mature OpnP protein contained 348 amino acid residues and shared 55% amino acid sequence identity with OmpF. Similar to ompF, opnP mapped between asnS and aspC. The 16 transmembrane beta-sheet structures and the internal loop 3 were highly conserved, while the remaining external loop domains were more divergent. Primer extension analysis identified the start site of transcription of opnP. A sigma 70-type promoter, a perfect 20 bp OmpR-binding site, and a binding site for the antisense molecule, micF RNA, were found in the upstream region of opnP. While the overall sequence identity of the asn-opnP-aspC region was high, the intergenic region between asnS and opnP had diverged markedly. The asnS-opnP region was 313 bp shorter than the intergenic region between asnS and ompF and lacked the OmpR-binding site that is required for ompF repression by high osmolarity in E. coli. Results from osmolarity-shift experiments indicated that OpnP was not repressed by high osmolarity. It was also found that OpnP was thermally regulated.
Amino Acid Sequence↗
[Risk of infection in endoscopy].
Infection is one of the hazards of endoscopic procedures. This long known risk has received major concern because of potential HIV infection. In the individual patient, both, patient related factors (such as the compromised host) and procedure related factors (such as tissue damage) determine the risk of infection. The potential for transmission of microorganisms from patient to patient or from the endoscopic equipment to the patient is reviewed. Common sources of infection and relevant microorganisms are listed. For prevention of transfer of infective agents through the contaminated endoscope the importance of thorough mechanical cleaning of the endoscope and adequate disinfection is stressed.
Cross Infection↗
[Preventing transmission of infection in endoscopy: hygienic maintainance of flexible endoscopes and measures for personal protection].
For prevention of transfer of infective agents by the contaminated endoscope the importance of thorough mechanical cleaning of the endoscope and adequate disinfection is stressed. Mode of action and side effects of liquid disinfectants as well as resistance of microorganisms (spores and some mycobacteria) to germicidal chemicals are mentioned. The different steps of disinfection procedures and potential causes of failure are discussed. Automatic disinfection systems are required for a higher degree of security of both patient and staff of the endoscopic unit. A regular control of the efficacy of the disinfection process is recommended and models for implementation are discussed. For prevention of occupationally acquired infection general precaution guidelines (use of gloves, prevention of needle-stick injuries) and vaccination programs are stressed.
Cross Infection↗