Biomedical subjects

M Kretzschmar

Publications and source records attributed to M Kretzschmar.

At least 55 records · Page 3Linked to original sources

PubMed1997

Concurrent partnerships and the spread of HIV.

OBJECTIVE: To examine how concurrent partnerships amplify the rate of HIV spread, using methods that can be supported by feasible data collection. METHODS: A fully stochastic simulation is used to represent a population of individuals, the sexual partnerships that they form and dissolve over time, and the spread of an infectious disease. Sequential monogamy is compared with various levels of concurrency, holding all other features of the infection process constant. Effective summary measures of concurrency are developed that can be estimated on the basis of simple local network data. RESULTS: Concurrent partnerships exponentially increase the number of infected individuals and the growth rate of the epidemic during its initial phase. For example, when one-half of the partnerships in a population are concurrent, the size of the epidemic after 5 years is 10 times as large as under sequential monogamy. The primary cause of this amplification is the growth in the number of people connected in the network at any point in time: the size of the largest "component'. Concurrency increases the size of this component, and the result is that the infectious agent is no longer trapped in a monogamous partnership after transmission occurs, but can spread immediately beyond this partnership to infect others. The summary measure of concurrency developed here does a good job in predicting the size of the amplification effect, and may therefore be a useful and practical tool for evaluation and intervention at the beginning of an epidemic. CONCLUSION: Concurrent partnerships may be as important as multiple partners or cofactor infections in amplifying the spread of HIV. The public health implications are that data must be collected properly to measure the levels of concurrency in a population, and that messages promoting one partner at a time are as important as messages promoting fewer partners.

Computer Simulation↗

PubMed1996

Modeling prevention strategies for gonorrhea and Chlamydia using stochastic network simulations.

A simulation model was used to study the spread of two sexually transmitted diseases (STDs), namely gonorrhea and genital infection with Chlamydia trachomatis. The model is based on a stochastic pair formation and separation process, which describes the underlying structure of the sexual contact pattern. It is implemented as a Monte Carlo simulation model. Spread of the STDs was modeled in an age-structured heterosexual population with a highly sexually active core group. Contact tracing strategies, screening of various subgroups, and the effect of condom use were compared. The authors conclude that contact tracing is very effective as a prevention strategy, that screening should be targeted to the highly active core group, that age is not sufficient as a determinant for high sexual activity to make screening of certain age groups useful, and, finally, that consistent condom use by a fraction of the population can contribute substantially to the prevention of STDs. All strategies proved more effective for gonorrhea than for Chlamydia prevention, which may explain the relatively high prevalence of Chlamydia found in many heterosexual populations.

Adolescent↗

PubMed1996

Measures of concurrency in networks and the spread of infectious disease.

An investigation is made into the impact of concurrent partnerships on epidemic spread. Starting from a definition of concurrency on the level of individuals, the authors define ways to quantify concurrency on the population level. An index of concurrency based on graph theoretical considerations is introduced, and the way in which it is related to the degree distribution of the contact graph is demonstrated. Then the spread of an infectious disease on a dynamic partnership network is investigated. The model is based on a stochastic process of pair formation and separation and a process of disease transmission within partnerships of susceptible and infected individuals. Using Monte Carlo simulation, the spread of the epidemic is compared for contact patterns ranging from serial monogamy to situations where individuals can have many partners simultaneously. It is found that for a fixed mean number of partners per individual the distribution of these partnerships over the population has a major influence on the speed of the epidemic in its initial phase and consequently in the number of individuals who are infected after a certain time period.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Regulation of hepatic glutathione metabolism and its role in hepatotoxicity.

The regulation of hepatic glutathione (GSH) metabolism have been reviewed. Key steps in the regulation of hepatic GSH are GSH biosynthesis, the GSH-redox-cycle, the cystathionine pathway, and the carrier-mediated export processes. Possible influences of xenobiotics on these different pathways are discussed. GSH fulfills several essential functions; detoxification of oxygen-derived free radicals, thioldisulfide exchange and storage and transfer of cysteine. GSH is present in all mammalian cells, but may be especially important for organs with intensive exposure to exogenous toxins such as the liver. Within the cell mitochondrial GSH is the main defense against physiological oxidative stress generated by cellular respiration and may be a critical target for toxins. Glutathione homeostasis of the organism is a highly complex process, which is predominantly regulated by the liver but also by skeletal muscle, lung and kidney.

Animals↗

PubMed1996

Luminol-and lucigenin-amplified chemiluminescence with rat liver microsomes. Kinetics and influence of ascorbic acid, glutathione, dimethylsulfoxide, N-t-butyl-a-phenyl-nitrone, copper-ions and a copper complex, catalase, superoxide dismutase, hexobarbital and aniline.

For the investigation of luminol (LM)-and lucigenin (LC)-amplified chemiluminescence (CL) in rat liver microsomes using both a liquid-scintillation counter (LKB/Wallac 1219 Rackbeta) and a Berthold luminometer (AutoLumat LB 953) optimal incubation mixtures and conditions and basic kinetics have been established. Whereas calibration curves for both LM- and LC-CL are performed with hydrogenperoxide (LC quantum yield is 6.25 fold higher as that of LM), distinct differences were revealed with microsomes, indicating that different reactive oxygen species (ROS) are determined: Both LM- and LC-CL follow the kinetics of enzymatic reactions in terms of dependence on protein and NADPH or NADH concentration, time course, temperature etc., but with differences. LM-CL does not work without addition of Fe2+, whereas LC-CL does. Both copper ions and copper bound in a complex abolish CL, LC-CL being much more sensitive. Isolated cytochrome P-450 (P450) and NADPH P450 reductase from liver of pheno-barbital treated rats alone proved to be inactive in LM-and LC-CL production, whereas te combination 1:1 without and with addition of lipid was highly active in both LM-and LC-CL. Ascorbic acid and glutathione as scavengers diminish both LM- and LC-CL in concentrations higher then 10(5). Dimethyl-sulfoxide (DMSO) was ineffective in LM-CL up to concentrations of 0.2 M, the very high concentration of 2 M diminished LM-CL only to 1/3. LC-CL was diminished starting at concentrations of 100 mM and at 2 M only 10% of maximum LC-CL was observed. The trap substance N-t-butyl-a-phenylnitrone (BNP) also diminished LC-CL more effectively than LM-CL. Clearcut differences were revealed by the addition of catalase and superoxide dismutase: both enzymes diminished LM-CL only, without any influence on LC-CL. Hexobarbital, a potent uncoupler of P450, enhances LM-CL fivefold, whereas LC-CL is barely influenced. Aniline (without uncoupling capability) decreased both LM-and LC-CL increasingly with increasing concentrations. Therefore the conclusion is drawn that LM-CL measures in liver microsomes predominantly superoxide anion radicals, whereas LC-CL is mainly a measure for microsomal hydroxyl radical formation or of reactive organic radicals. With microsomes of phenobarbital and beta-naphthoflavone treated rats CL was much higher but in principle the same kinetic characteristics could be shown. All results on microsomes were obtained uniformly with the liquid scintillation counter and the Berthold luminometer, the letter being much more effective and more sensitive.

Acridines↗

PubMed1996

Reduction of ischemia-reperfusion syndrome after abdominal aortic aneurysmectomy by N-acetylcysteine but not mannitol.

BACKGROUND: Abdominal aortic aneurysmectomy results in a general ischemia-reperfusion syndrome accompanied by an acute rise in mean pulmonary artery pressure (MPAP). Severe and sometimes fatal postoperative cardiopulmonary complications have been described. METHODS: This pilot study examined whether N-acetyl-cysteine (NAC), a precursor of the most important physiological antioxidant glutathione (reduced form: GSH; oxidized form: GSSG), or the hydroxyl radical scavenger mannitol (MAN) modifies these events. The patients received 150 mg/ kg b.m.NAC (n = 9) 30 minutes before infrarenal aortic clamping or 500 mg/kg b.m. MAN (n = 10) 10 minutes before declamping. 11 patients had no additional treatment (control). RESULTS: In the control group, a significant increase in plasma levels of oxidized glutathione and lipid peroxides was observed after declamping. Additionally, a significant increase in plasma levels of the stable metabolites of thromboxane (TXB2) and prostacyclin (6-keto-PGF1 alpha) was measureable after declamping. There was a transient increase in MPAP and pulmonary vascular resistance (PVR), both of which returned to normal values within 20 minutes. Six hours after surgery, pulmonary dysfunction was manifest by increase in the intrapulmonary shunt fraction. Relative to the control group, NAC pretreatment led to a complete lack of changes in plasma lipid peroxide, thromboxane and prostacyclin levels after declamping; there was a significant increase in plasma GSH concentration persisting over a period of 12 hours. MPAP, PVR and Qs/QT values were unchanged. MAN pretreatment showed similar effects on the parameters obtained in the acute phase after declamping like the control group. CONCLUSIONS: Pretreatment with NAC, but not mannitol, may help prevent ischemia-reperfusion syndrome following aortic clamping.

Acetylcysteine↗

PubMed1996

[Endotoxinemia and multiple organ failure after polytrauma].

Despite successful management of early complications in polytraumatized patients and obvious reduction of early death, lethality in the late course of the disease--frequently as a result of multiple organ failure (MOF)--remains generally unaffected. Concerning the pathogenesis of sepsis and MOF, there is some evidence that a central role is played by endotoxin. A series of 32 patients with severe polytraumatic injury (Hannover Polytrauma Score > 20 points) comprised the study group. Endotoxin was measured hourly over the first 24 hours. The first measuring point was four hours after injury at the latest. Endotoxin levels were determined by a quantitative turbidimetric limulus assay. The Goris MOF score reached between the 8th and 10th day after injury was used for evaluation of the severity of MOF. Thirty of the 32 patients showed episodes of endotoxemia during the measuring period. There was a strong correlation between observed endotoxin peak concentrations, on the one hand, and outcome as well as positive predictive value (PPV) concerning development of MOF, on the other hand. If the peak concentration was greater than 10 pg/ml, the PPV reached 100%. No patient survived a peak concentration greater than 12 pg/ml. Endotoxemia during the early phase after polytraumatic injury is a frequent phenomenon. It appears to be possible that measurement of endotoxin peak concentration during the early phase gives some indication of the development of MOF and the outcome of these patients.

APACHE↗

PubMed1996

[Severe course of ornithosis and its intensive care and diagnostic problems--a case report].

Ornithosis is still a life-threatening illness unless diagnosed early and adequately treated with antibiotics. Diagnosis, however, is difficult because often no direct contact with birds is obvious. We report on the course of a severe case of ornithosis in a 45-year-old man who had no previous health problems. Infection with Chlamydia psittaci probably occurred by inhaling of contaminated dust produced by flocks of wild pigeons. A special feature of the case is that commonly used serological tests (complement fixation reaction, CFR; ELISA) failed to yield clear results. Since propagation of Chlamydia psittaci requires special biological laboratory containment facility no. 3, we were able to detect the pathogen in faeces, blood, and urine using the direct immunofluorescence antibody technique (DIFT) and a modified peroxidase antiperoxidase technique (PAP). A lot of Chlamydia psittaci was found. These results were verified by electron microscopy. As a result, the treatment could be quickly adjusted to the application of doxycyclin, which led to a rapid improvement in the patient's condition. This direct detection of Chlamydia psittaci by DIFT, the PAP technique or electron microscopy, also in faeces, blood and urine specimens, represents a useful addition to the usual microbiological methods for the diagnosis of this pathogen.

Anti-Bacterial Agents↗

PubMed1994

A novel mediator of class II gene transcription with homology to viral immediate-early transcriptional regulators.

Our investigations of mammalian class II gene transcription resulted in identification, purification, and cloning of the corresponding cDNA of a cellular factor (p15) that mediates the effects of several distinct activators on transcription in vitro. Functional deletion analyses revealed a bipartite structure of p15 comprising an amino-terminal regulatory domain and a carboxy-terminal cryptic DNA-binding domain. We provide evidence that activity of p15 is controlled by protein kinases that target the regulatory domain. Structural and functional similarities, including sequence homology to domains essential for cofactor function, cofactor activity, promiscuity with respect to transcriptional activators, and interactions with components of the basal transcription machinery, relate this novel cellular cofactor to viral immediate-early transcriptional regulators.

Amino Acid Sequence↗

PubMed1994

The basic reproduction ratio R0 for a sexually transmitted disease in a pair formation model with two types of pairs.

We study a model for pair formation and separation with two types of pairs which differ in average duration. A fraction f of all newly formed pairs have a long duration (denoted by "steady"), the remaining fraction 1-f have a short duration ("casual"). This distinction is motivated by data about the survival times of partnerships in a sociological survey. In this population we consider a sexually transmitted disease, which can have different transmission rates in steady and in causal partnerships. We investigate under which conditions an epidemic can occur after introduction of the disease into a population where the process of pair formation and separation is at equilibrium. If there is no recovery we can compute an explicit expression for the basic reproduction ratio R0; if we take recovery into account we can derive a condition for the stability of the disease-free equilibrium which is equivalent to R0 < 1. We discuss how R0 depends on various model parameters.

Epidemiologic Methods↗

PubMed1994

Social transmission routes of HIV. A combined sexual network and life course perspective.

A combined sexual network and lifecourse perspective is proposed as a basis for reconstructing the sexological infrastructure of HIV dissemination. Necessary data are drawn from a representative sample survey of 1001 adults (age range 18-50 years) in the Netherlands. Heterosexual respondents' behavioural risk level, expressed in the number of unprotected sexual interconnections with primary and secondary partners, is found to be related to both age and relational status, though these variables cannot fully predict risk. While those under 24 years of age are over-represented in the larger components of sexual networks, above 32 years of age there is a small group who follow a lifestyle of regularly changing sexual partners.

Adolescent↗

PubMed1994

RNA polymerase II cofactor PC2 facilitates activation of transcription by GAL4-AH in vitro.

We have isolated from a crude Hela cell cofactor fraction (USA) a novel positive cofactor that cooperates with the general transcription machinery to effect efficient stimulation of transcription by GAL4-AH, a derivative of the Saccharomyces cerevisiae regulatory factor GAL4. PC2 was shown to be a 500-kDa protein complex and to be functionally and biochemically distinct from native TFIID and previously identified cofactors. In the presence of native TFIID and other general factors, PC2 was necessary and sufficient for activation by GAL4-AH. Cofactor function was specific for transcriptional activation domains of GAL4-AH. The repressor histone H1 further potentiated but was not required for activation of transcription by GAL4-AH. On the basis of the observation that PC2 exerts entirely positive effects on transcription, we propose a model in which PC2 increases the activity of the preinitiation complex in the presence of an activator, thereby establishing a specific pathway during activation of RNA polymerase II.

Blotting, Western↗

PubMed1993

Identification of human DNA topoisomerase I as a cofactor for activator-dependent transcription by RNA polymerase II.

The transcriptional activation of eukaryotic class II genes by sequence-specific regulatory proteins requires cofactors in addition to the general transcription factors. One cofactor (termed PC3) was purified from HeLa cells and identified by sequence analysis and functional assays as human DNA topoisomerase I (EC5.99.1.2). Under identical conditions PC3 mediates both a net activation of transcription by the acidic activator GAL4-AH and repression of basal transcription, thereby leading to a large induction of transcription by the activator. PC3-mediated activation of transcription is dependent on the presence of both the GAL4-AH activation domain and the TATA-binding protein (TBP)-associated-factors (TAFs) in natural transcription factor TFIID, while repression of basal transcription is observed with either TFIID or the derived TBP alone. These results suggest novel functions, apparently through distinct mechanisms, for human DNA topoisomerase I in the regulation of transcription initiation by RNA polymerase II.

Amino Acid Sequence↗

PubMed1993

Aggregated distributions in models for patchy populations.

We investigate a model describing immigration, birth, and death of parasites on a dynamic host population. The model can also be interpreted as describing a herbivore population distributed on discrete patches of vegetation. We derive differential equations for the total number of hosts/patches and the mean number of parasites/herbivores per host/patch. The equations explicitly involve the variance-to-mean ratio of the distribution. It is shown that the positive equilibrium is stable if and only if the variance-to-mean ratio as a function of the mean increases with increasing mean. Thus aggregation of the parasites alone is not sufficient to stabilize the system; it is rather the density-dependent increase in parasite mortality due to a higher aggregation at higher mean parasite loads that causes stability. From this it follows that introducing a distribution with a constant clumping parameter into the model artificially stabilizes the steady state. We derive a three-dimensional model based on an assumption about the form of the distribution of the parasites on the hosts, but without introducing additional parameters into the model. We compare stability results for this model for different types of aggregated distributions and show that the underlying distribution determines the qualitative results about the stability of the equilibrium.

Animals↗

PubMed1993

Age dependent different consequences of bilateral nephrectomy (NX) in rats.

Adult rats survived the removal of both kidneys (NX) for about 48 hours; survival time was distinctly lower in 10- and 20-day-old rats (about 24 hrs). Some of the measured parameters indicate age dependent differences in uremic impairment. In the prefinal period after NX blood urea nitrogen concentrations were distinctly higher in adult than in young rats. After nephrectomy diminution of the concentrations of GSH and GSSG in liver tissue is more distinct in adult than in young rats. Similarly, 24 hrs after NX the content of lipid peroxides in liver tissue was higher in adult than in 10- and 20-day-old rats. Furthermore, the prolongation of bleeding time in uremic rats was more distinct in adult than in young rats. The following parameters indicate uremic impairment clearly, but age dependent differences do not exist: Increase of potassium concentration in plasma, enhanced activities of liver specific enzymes in plasma, reduced concentration of various amino acids in plasma and distinct increase in plasma concentration of taurine.

Age Factors↗

PubMed1993

Enzymes of glutathione synthesis in dog skeletal muscles and their response to training.

The glutathione synthesizing enzymes, gamma-glutamyl cysteinyl synthetase and glutathione synthetase, were found in all skeletal muscles studied in dogs. Both occurred also in the liver, but only the former in the lung. The influence of physical training on these enzyme activities was also investigated. For 30 weeks the dogs ran 5 days week-1 on a treadmill at a 15 degrees uphill grade. A 1.5- to 2-fold increase in the gamma-glutamyl cysteinyl synthetase and 3-fold increase in the glutathione synthetase activities was observed in muscles affected by the training procedure (m. triceps, m. extensor carpi radialis and m. gastrocnemius). No training effect could be observed in the splenius and longissimus dorsi muscles or in the liver. The training increased total glutathione levels in the lung and gastrocnemius muscle as well as in the plasma. Glutathione disulfide levels were not altered. Acute physical exercise significantly decreased the plasma total glutathione concentrations in the trained dogs. The results indicate a training responsive adaptation of glutathione system in skeletal muscle.

Animals↗

PubMed1993

Aging, training and exercise. A review of effects on plasma glutathione and lipid peroxides.

Changes in plasma glutathione (reduced form: GSH; oxidised form: GSSG) and lipid peroxides (LPO) levels occur with aging, training and acute physical exercise. Sources of plasma GSH, GSSG and LPO include the liver and skeletal muscle. Aging appears to be accelerated because of a decrease in the antioxidant capacity of tissues reflected in a decreased plasma GSH level. This age-dependent change could be partly compensated by physical training. Skeletal muscle appears to be able to deliver GSH into circulation with the adaptation of muscle to exercise training reflected in an increased plasma GSH level in the trained subject. Decreased plasma GSH concentration following physical exercise demonstrates increased GSH consumption in skeletal muscle resulting in a reduced export rate from muscle into plasma. The GSH system is able to effectively protect tissues against lipid peroxidation initiated by oxygen-derived free radicals produced in the intermediate metabolism during exercise. It can be assumed that the rate of this free radical production is a function of oxygen flow through organ and muscle tissue.

Aging↗

PubMed1992

The c-rel protooncogene product c-Rel but not NF-kappa B binds to the intronic region of the human interferon-gamma gene at a site related to an interferon-stimulable response element.

Interferon-gamma (IFN-gamma) is an important immunoregulatory protein that is expressed usually only in large granular lymphocytes and T cells. The gene encoding IFN-gamma was previously found to contain an intronic enhancer element that was not tissue-specific in its activity, despite the restricted expression of the intact IFN-gamma-encoding gene. Using nuclear extracts from the human T-cell line Jurkat, we have now identified two protein-binding regions in this intronic enhancer element. One of the protected regions has strong partial identify to the NF-kappa B site present in the promoter region of the human interleukin 2-encoding gene. Based on this observation and recent reports of the interaction of the c-rel protooncogene product (c-Rel) with NF-kappa B sites, we determined whether c-Rel could interact with the intronic enhancer element in the human IFN-gamma genomic DNA. Most surprisingly, gel-shift analysis, using c-Rel expressed in Escherichia coli established that c-Rel binds specifically to the IFN-gamma intronic DNA but not to the interleukin 2-like NF-kappa B site. Additional studies with antibodies prepared against c-Rel peptides verified specificity of the interaction of c-Rel with this binding site. In addition, using an affinity-purified p50 subunit of the NF-kappa B complex, we observed that the p50 protein did not bind to this additional c-Rel-binding site. Furthermore, nucleotide sequence analysis of this DNA region revealed a strong similarity of the additional c-Rel-binding site to a previously identified IFN-stimulable response element. These data show that c-Rel can interact with DNA regions distinct from that recognized by NF-kappa B and may, in fact, be involved in transcriptional regulation of the IFN-stimulable genes via the IFN-stimulable response element.

Base Sequence↗