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Biomedical subjects

M Kretzschmar

Publications and source records attributed to M Kretzschmar.

At least 37 records · Page 2Linked to original sources
PubMed2001

Procalcitonin following elective partial liver resection--origin from the liver?

BACKGROUND: The origin of the inflammatory peptide procalcitonin (PCT) is still unknown. In the present study PCT concentrations in arterial and hepatic-venous blood were examined in patients undergoing elective partial liver resection (LR) using a fiberoptic pulmonary arterial catheter placed in a liver vein to obtain further information on the origin of PCT. METHODS: In 28 patients (21 male/7 female; average age of 58.8+/-8.8 years) undergoing LR, arterial and hepatic venous PCT concentrations were measured during 24 h perioperatively. The parallel blood withdrawals occurred immediately before the Pringle maneuver (Hx), 2 min, 1, 2, 6, 12, and 24 h after Hx. Over the whole period, the oxygen saturation in hepatic venous blood (ShvO2) was monitored. PCT concentrations were assayed by immunoluminometry. RESULTS: We observed a significant increase in PCT concentration already 6 h after Hx compared to the values before Hx. Twenty-four hours after Hx we found the highest plasma concentrations. It was conspicuous that hepatic venous PCT concentrations were always higher than the arterial ones (significantly from the 6th hour after Hx). There was no correlation between the courses of ShvO2 and PCT rise. A significant correlation was verified between Hx duration and PCT concentration measured 24 h after Hx both in the hepatic venous and arterial blood. CONCLUSIONS: The results of our investigation can be interpreted as evidence that liver (or the hepatosplanchnicus?) is a source of PCT. The mechanism of PCT induction cannot be clarified by our study: whether the induction of PCT was caused by an endotoxin translocation during the impeded splanchnic outflow or by the direct surgery-induced lesion (hypoxia) of the liver remains unclear. However, the latter appears more probable because of the observed correlation between Hx duration and PCT concentration rise.

Calcitonin↗
PubMed2001

[Poisoning with sleep supporting drugs].

Emergencies caused by acute poisoning amount to 3-5% of the actions carried out by the emergency medical service. Sleep supporting drugs have a 35% part in the acute drug-induced poisoning, primarily within the framework of suicidal or parasuicidal actions. In this case, benzodiazepines occupy a top position, followed by H1-antihistaminic agents with strong sedative effects, and the so-called anxiolytic agents of the "second generation". In general, intoxication with sleep supporting drugs lead to disturbances of consciousness with different degrees of seriousness. Careful (external) anamnesis, inspection of the environment and clinical investigations could be helpful to evaluate the diagnosis. Hypoglycemia and neurological illnesses are to be excluded differential diagnostically. Preclinical therapy follows the "five finger rule" (stabilization of the vital functions, detoxification, antidote therapy, asservation, transportation). Specific procedures (preclinical stomach lavage, antidote therapy) are indicated in rare cases, only (mainly mixed intoxication with ethanol). Subsequent therapeutic procedures under clinical conditions are demonstrated using selected examples.

Diagnosis, Differential↗
PubMed2000

Transforming growth factor-beta and breast cancer: Transforming growth factor-beta/SMAD signaling defects and cancer.

Transforming growth factor-beta (TGF-beta) is a tumor suppressor, the function of which is compromised in many types of human cancer, including breast cancer. The tumor suppressive effects of TGF-beta are caused by potent inhibition of cell proliferation due to cell cycle arrest in the G1 phase. Such antiproliferative responses are mediated by a signaling system that includes two types of cell surface receptors and intracellular signal transducers, the SMAD proteins. Different molecular mechanisms can lead to loss of antiproliferative TGF-beta responses in tumor cells, including mutations in components of the signaling system and inhibition of the SMAD signaling pathway by aberrant activities of various regulatory molecules. Some of these mechanisms will be discussed, with emphasis on their potential involvement in breast tumorigenesis.

Breast Neoplasms↗
PubMed2000

Waning immunity and sub-clinical infection in an epidemic model: implications for pertussis in The Netherlands.

In The Netherlands, an epidemic outbreak of pertussis took place in 1996-1997. Understanding of the causes of the epidemic is hampered by the fact that many cases of infection with Bordetella pertussis go by unnoticed, and by the fact that immunity against infection does not last lifelong. Motivated by these observations, we develop and analyze an age-structured epidemic model that takes these factors into account. A distinction is made between infection in immunologically naive individuals, and infection in individuals whose immune system has been primed before by infection or vaccination. While the former often lead to severe symptoms and thus are more often diagnosed and notified, the latter are largely sub-clinical. The main questions are: (1) to what extent do sub-clinical infections contribute to the circulation of B. pertussis; and (2) what might be the causes for the recent epidemic? To answer these questions, we first present a new method to estimate the force of infection from notification data. The method is applied to the 1988-1995 case notification data from The Netherlands. Estimates of the force of infection vary greatly, depending on the rate at which immunity is lost, and on the fraction of sub-clinical infections. For the 1988-1995 period, our analysis indicates that if immunity is lost at a small rate and if a majority of infections is sub-clinical, the contribution of infection in adults to the transmission process cannot be neglected. Our results furthermore indicate that a decrease in the duration of protection after vaccination due to a change in the pathogen is the most likely factor to account for the 1996-1997 epidemic.

Adolescent↗
PubMed2000

Contact tracing in stochastic and deterministic epidemic models.

We consider a simple unstructured individual based stochastic epidemic model with contact tracing. Even in the onset of the epidemic, contact tracing implies that infected individuals do not act independent of each other. Nevertheless, it is possible to analyze the embedded non-stationary Galton-Watson process. Based upon this analysis, threshold theorems and also the probability for major outbreaks can be derived. Furthermore, it is possible to obtain a deterministic model that approximates the stochastic process, and in this way, to determine the prevalence of disease in the quasi-stationary state and to investigate the dynamics of the epidemic.

Communicable Diseases↗
PubMed2000

The pre-vaccination epidemiology of measles, mumps and rubella in Europe: implications for modelling studies.

Data on the pre-vaccination patterns of infection for measles, mumps and rubella are collated from a number of European countries in order to compare the epidemiology of the three viruses. Key epidemiological parameters, such as the age-specific force of infection and the basic reproduction number (R0) are estimated from case notification or serological data using standard techniques. A method is described to compare force of infection estimates derived from serological data. Analysis suggests that the pre-vaccination patterns of measles and mumps infection in the different countries were similar. In contrast, the epidemiology of rubella was highly variable between countries. This suggests that it may be acceptable to use parameter values estimated from other countries to model measles and mumps transmission, but that this approach to modelling rubella transmission requires more caution. Estimates of R0 depend on underlying mixing assumptions. Constraints were placed on R0 estimates by utilising knowledge of likely mixing patterns. The estimates for R0 were highest for measles, intermediate for mumps, and generally lowest for rubella. Analysis of within- and between-age-group transmission rates suggested that mumps transmission tends to be more concentrated within young children than the other two viruses. The implications for the design of immunization programmes are that mumps may be the easiest to control via infant immunization since it is predominantly transmitted between the very young and the variability in rubella epidemiology requires that careful consideration of the possible effects of vaccination options should be made using local data when planning rubella immunization programmes.

Adolescent↗
PubMed2000

Cost-effectiveness of screening programs for Chlamydia trachomatis: a population-based dynamic approach.

BACKGROUND: Models commonly used for the economic assessment of chlamydial screening programs do not consider population effects. GOAL: To develop a novel dynamic approach for the economic evaluation of chlamydial prevention measures and to determine the cost-effectiveness of a general practitioner-based screening program. STUDY DESIGN: The dynamic approach was used to estimate the cost-effectiveness of a screening program for the first 10 years of screening in The Netherlands. Screening involved a ligase chain reaction test on urine followed by standardized therapies and partner referral. Eligible persons were sexually active, 15 to 24 years, visited a general practitioner, and had no symptoms of sexually transmitted diseases. The heterosexual model population, which consisted of persons 15 to 64 years, had a total chlamydial prevalence of 4.1% before screening. Screening effects on chlamydial incidence were computed by using a population-based stochastic simulation model. Incidence data were connected with a decision analysis model to determine the health effects of the program. The net costs of the program were calculated (investment costs minus averted costs, in 1997 US$) from a societal perspective and expressed per major outcome averted (symptomatic pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, infertility, neonatal pneumonia). RESULTS: Unlike the standard static approach, our model adequately addresses dynamic processes such as chlamydial transmission and the impact of screening programs on chlamydial incidence in the population. During the first 10 years of screening, the investigated program yields savings of US $492 or US $1,086 per major outcome averted, excluding or including indirect costs, respectively. These results depend on chlamydial prevalence and partner referral. CONCLUSIONS: The cost-effectiveness of chlamydial screening programs seems best to be determined by using dynamic modeling on a population basis. In addition to preventing negative health outcomes, the investigated screening program may save costs.

Adolescent↗
PubMed2000

Sexual network structure and sexually transmitted disease prevention: a modeling perspective.

BACKGROUND: Mathematical modeling techniques are being used increasingly to plan public health policy for the prevention of sexually transmitted diseases. GOAL: An introduction to various aspects of network structure and sexually transmitted disease prevention using mathematical and simulation models. STUDY DESIGN: A short overview is given about some modeling approaches that are presently available. The effect of partnership duration on the spread of sexually transmitted diseases is discussed in the context of pair-formation models. Network models, which take concurrent partnerships into account, are discussed as a natural extension of pair-formation models. RESULTS: Results obtained by applying different modeling approaches to analyzing the efficacy of contact tracing in reducing the prevalence of sexually transmitted diseases are summarized. CONCLUSION: Partnership duration and network structure should be taken into account when estimating the impact of sexually transmitted disease prevention. Contact tracing can contribute significantly to reducing incidence and prevalence of sexually transmitted diseases. modeling has to be developed further to gain a better understanding of the relationship of network structure and the spread of specific sexually transmitted diseases.

Female↗
PubMed2000

[Initiation of lipid peroxidation (LPO) in blood during intraoperative mechanical autotransfusion--is hepatotoxicity of lipid peroxidation products of clinical significance?].

Machine autotransfusion using cell-saver is a well-established method of saving homologous blood during extensive surgical procedures. The processing of blood may induce the initiation of lipid peroxidation (LPO) with the release of hepatotoxic products. A series of 42 patients undergoing primary (n = 20) or revision (n = 22) hip arthroplasty comprised the study group. Patients received an average of 1,260 ml of autologous blood and 2.2 units of homologous packed cells. The concentration of thiobarbituric acid reactive substances (TBARS) as LPO metabolites was measured in the patients' plasma, in the autologous packed cells as well as in the supernatants of the cell-saver-processed blood. Additionally, parameters of iron metabolism, haemoglobin levels, haematocrit as well as the activities of so-called liver enzymes aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase and cholinesterase were determined. An initiation of LPO was detectable during the process of machine autotransfusion, but this took place mainly ex vivo. High concentrations of TBARS were detectable in the supernatants after cell-separation processing. We observed a decline in haemoglobin concentration and haematocrit during the perioperative period. Postoperatively, we found a significant iron deficiency as a consequence of the perioperative blood loss. There was not sufficient evidence of a postoperative liver disorder induced by toxic metabolites of LPO. To sum up, there is only a low contamination of the organism with LPO products during the process of machine autotransfusion. Therefore, an induction of liver damage seems to be improbable.

Adult↗
PubMed1999

A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras.

TGFbeta can override the proliferative effects of EGF and other Ras-activating mitogens in normal epithelial cells. However, epithelial cells harboring oncogenic Ras mutations often show a loss of TGFbeta antimitogenic responses. Here we report that oncogenic Ras inhibits TGFbeta signaling in mammary and lung epithelial cells by negatively regulating the TGFbeta mediators Smad2 and Smad3. Oncogenically activated Ras inhibits the TGFbeta-induced nuclear accumulation of Smad2 and Smad3 and Smad-dependent transcription. Ras acting via Erk MAP kinases causes phosphorylation of Smad2 and Smad3 at specific sites in the region linking the DNA-binding domain and the transcriptional activation domain. These sites are separate from the TGFbeta receptor phosphorylation sites that activate Smad nuclear translocation. Mutation of these MAP kinase sites in Smad3 yields a Ras-resistant form that can rescue the growth inhibitory response to TGFbeta in Ras-transformed cells. EGF, which is weaker than oncogenic mutations at activating Ras, induces a less extensive phosphorylation and cytoplasmic retention of Smad2 and Smad3. Our results suggest a mechanism for the counterbalanced regulation of Smad2/Smad3 by TGFbeta and Ras signals in normal cells, and for the silencing of antimitogenic TGFbeta functions by hyperactive Ras in cancer cells.

Animals↗
PubMed1999

Synthesis and autoradiographic evaluation of a novel high-affinity Tc-99m ligand for the 5-HT2A receptor.

The synthesis and in vitro autoradiography of a novel Tc-99m ligand with subnanomolar affinity to the 5-HT2A receptor is reported. The complex combines the 4-(4-fluoro)-benzoyl piperidine portion derived from the 5-HT2A receptor antagonist ketanserin with a neutral oxotechnetium(V) chelate in form of a mixed ligand "3 + 1" unit containing the SNS/S donor set. The analogous rhenium compound has been synthesized as a surrogate for the Tc-99m complex for use in receptor binding assays and for complete structural characterization. In competition experiments the Tc-99 complex as well as its Re analogue display subnanomolar affinity toward the 5-HT2A receptor (Ki 0.44 nM for Tc, 0.25 nM for Re). The subnanomolar 5-HT2A receptor binding of the Re complex was confirmed by functional in vitro antagonism of contractile effects evoked by 5-HT in rat arterial tissue. Re 1 inhibited 5-HT-induced, 5-HT2A receptor-mediated contractions of isolated rat tail artery in a competitive fashion and possessed nanomolar affinity (pA2 = 9.08, pA2 representing the negative decadic logarithm of the Re 1/5-HT2A-receptor dissociation constant [mol/L]). Like ketanserin, Re 1 displayed moderate affinity for adrenergic alpha1D (pA2 = 8.23) and histamine H1 receptors (pA2 = 8.00), and was >600-fold up to 10,700-fold less active at several neurotransmitter receptor subtypes. In vitro autoradiographic studies clearly indicate the accumulation of the Tc-99m compound in 5-HT2A-receptor-rich areas of the brain. This enrichment can be blocked by 5-HT2A receptor antagonists such as mianserin and ketanserin and is therefore specific.

Animals↗
PubMed1998

Modelling the spread of HIV in social networks of injecting drug users.

OBJECTIVE: To explore the risk of a future rise of HIV prevalence in populations of injecting drug users (IDU) with low HIV prevalence but continuing risk behaviour, and to study the potential influence of prevention measures on HIV incidence. METHODS: A stochastic simulation model was used to describe a network of long-term buddy relationships in a population of IDU. HIV transmission took place when borrowing injecting equipment from an infected buddy or stranger. The probability of transmission depended on the duration of infection. Individuals remained in the population on average for 10 years. Two surveys amongst IDU in The Netherlands containing information about risk behaviour were used to estimate model parameters. We investigated the effect of different prevention strategies. RESULTS: Below a threshold sharing frequency the epidemic never takes off; above the threshold there is a large stochastic variation in prevalence. After reduction of risk behaviour, HIV prevalence decreases very slowly. Reducing sharing with strangers is more effective than reducing the overall sharing frequency. Prevention focused on new IDU greatly reduces HIV incidence. Reduction of sharing frequency in HIV-positive IDU has no significant influence on HIV incidence at HIV testing rates of 10 and 50% per year, if infectivity is highest during primary infection. CONCLUSIONS: A stabilization of HIV prevalence does not exclude the possibility of a future rise. Predictions about the future course of an epidemic are inherently uncertain. The effect of prevention programmes on HIV prevalence only becomes visible on a long time-scale. Social networks of IDU play an important role in transmission dynamics and success of prevention.

HIV Infections↗
PubMed1998

The effect of pair formation and variable infectivity on the spread of an infection without recovery.

For the spread of an infection without recovery we compare the properties of a model in which contacts are assumed to be instantaneous and every contact is with a new partner to a model with an explicit description of partnership formation and duration. We investigate the dynamic behaviour at the beginning of the epidemic, the exponential growth phase and the endemic equilibrium in a population with a simple demographic process. Comparisons are made with the assumption that the basic reproduction ratio R0 is equal for both models. In a second step we introduce variable infectivity into both models and investigate how that interacts with the process of pair formation and partnership duration. The main results are: If partnership duration is taken into account, then (a) the prevalence may initially decrease, even if R0 > 1; (b) the exponential growth rate is lower than in a model without partnership duration; (c) the endemic equilibrium is higher than in a model without partnership duration. Furthermore we show that for a model with positive partnership duration for one value of R0 one might have more than one corresponding epidemic growth rate and endemic steady state. This implies that one cannot estimate R0 from the endemic level without further information on the partnership process. Finally we demonstrate that even for a very low value of per contact infectivity in the second stage of infection, as has been postulated for HIV-infection, transmission during the second stage may contribute significantly to the spread of the epidemic due to the long duration of the second stage. Therefore, reduction of the high infectivity in the short first stage of infection only affects R0 markedly if average partnership duration is short.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Plasma levels of glutathione, alpha-tocopherol and lipid peroxides in polytraumatized patients; evidence for a stimulating effect of TNF alpha on glutathione synthesis.

Prognosis and outcome of polytraumatized patients are determined by the possible development of multiple organ failure (MOF). Among the direct traumatic organ damage, it is caused by a systemic inflammatory reaction. This might be triggered by an activation of the inflammatory mediator cascade following hemorrhagic-traumatic shock as well as by oxygen-derived free radicals (ROS). The aim of our present study was to answer the following questions: 1. Is the "oxidative stress" measurable during the development of MOF after polytraumatic injury? 2. Is there a relation between the activation of the inflammatory mediator cascade and changes of the organism's antioxidative system? The study group included 26 patients (15 survivors, 11 non-survivors) suffering from severe polytraumatic injury (Hannover Polytrauma Score 12-63 points). Plasma levels of reduced (GSH) and oxidized (GSSG) glutathione alpha-tocopherol (TOC), lipid peroxides (expressed in terms of thiobarbituric acid reagible substances = TBARS), and tumor necrosis factor alpha (TNF) were measured each day from the point of admission on the ICU until the discharge or death of the patients. The following results were obtained: Independent from the outcome, we observed a continuous loss of plasma sulfhydryl groups and TOC. In the patients developing a MOF score > 5 on 10th day after injury (n = 6), a significant increase in plasma GSSG level was measurable. Additionally, a total loss of plasma GSH was seen in some of these patients indicating the collapse of the GSH-dependent antioxidative system. Similar changes were never observed in patients with MOF score < or = 5 on 10th day after injury (n = 15). In this group, a significant correlation between plasma TNF peaks and short time GSH boosts was obtained as a possible indicative for a stimulating effect of TNF on GSH synthesis. It can be concluded that processes of oxidative stress in connection with a consumption of endogenic antioxidants might be able to promote the development of MOF after polytraumatic injury.

Adolescent↗
PubMed1998

SMADs: mediators and regulators of TGF-beta signaling.

The discovery of SMAD proteins has allowed the delineation of a mechanism by which TGF-beta and related growth factors convey their signals from membrane receptors all the way into the nucleus. SMADs are directly phosphorylated and activated by the receptors and then form heteromeric SMAD-SMAD complexes that move into the nucleus where they orchestrate transcriptional responses. In rapid succession, recent reports have identified different modes of SMAD regulation by phosphorylation and have defined the SMAD domains that mediate SMAD interactions, binding to DNA or transcriptional activation. The recent discovery of antagonistic SMADs and regulatory crosstalk with Ras/MAP-kinase pathways add to our rapidly expanding understanding of this major regulatory network.

Animals↗
PubMed1997

Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1.

The growth factor TGF-beta, bone morphogenetic proteins (BMPs) and related factors regulate cell proliferation, differentiation and apoptosis, controlling the development and maintenance of most tissues. Their signals are transmitted through the phosphorylation of the tumour-suppressor SMAD proteins by receptor protein serine/threonine kinases (RS/TKs), leading to the nuclear accumulation and transcriptional activity of SMAD proteins. Here we report that Smadl, which mediates BMP signals, is also a target of mitogenic growth-factor signalling through epidermal growth factor and hepatocyte growth factor receptor protein tyrosine kinases (RTKs). Phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of Smad1, and is catalysed by the Erk family of mitogen-activated protein kinases. In contrast to the BMP-stimulated phosphorylation of Smad1, which affects carboxy-terminal serines and induces nuclear accumulation of Smad1, Erk-mediated phosphorylation specifically inhibits the nuclear accumulation of Smad1. Thus, Smadl receives opposing regulatory inputs through RTKs and RS/TKs, and it is this balance that determines the level of Smad1 activity in the nucleus, and so possibly the role of Smad1 in the control of cell fate.

Amino Acid Sequence↗
PubMed1997

The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase.

Bone morphogenetic proteins (BMPs) are members of the TGF-beta family that regulate cell proliferation, apoptosis, and differentiation, and participate in the development of most tissues and organs in vertebrates. Smad proteins function downstream of TGF-beta receptor serine/threonine kinases and undergo serine phosphorylation in response to receptor activation. Smad1 is regulated in this fashion by BMP receptors, and Smad2 and Smad3 by TGF-beta and activin receptors. Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro. Mutation of these carboxy-terminal serines prevents several Smad1 activation events, namely, Smad1 association with the related protein DPC4, accumulation in the nucleus, and gain of transcriptional activity. Similar carboxy-terminal serines in Smad2 are required for its phosphorylation and association with DPC4 in response to TGF-beta, indicating the generality of this process of Smad activation. As a direct physiological substrate of BMP receptors, Smad1 provides a link between receptor serine/threonine kinases and the nucleus.

Activin Receptors↗