Radiochemotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
C Schäfer
Publications and source records attributed to C Schäfer.
[A 52-year-old patient with positive troponin, iron deficiency anemia and known sarcoidosis].
We report on a 52-year-old female patient with recurrent neurosarcoidosis and an "atypical" course of celiac disease, with mild clinic features, positive IgA-antibodies and histology. In our patient, the IgA-antibodies led to a false positive troponin I test, and we initially suspected an acute coronary syndrome. With dietary treatment of the celiac disease, the antibodies decreased and the troponin I test became negative. The coincidental occurrence of sarcoidosis and "potential" celiac disease (positive antibodies only) has been reported. The coincidence of an "atypical" celiac disease and sarcoidosis is rare.
Alanine Transaminase↗
[Instruction in medical ethics during clinical training for medical students: report on experience in radio-oncology].
The article gives a review of the current state of education in medical ethics in Germany. The issue is considered from the viewpoint of radio-oncology. Both the pertinent literature and our own experience in teaching medical ethics are presented. In October 2003, medical ethics was integrated into the curriculum of medicine. The aim was to train competence in the field of personal attitudes and to intensify skills of moral reasoning. Our own experiences are positive, which is in accordance with the reports of other working groups. Most of the students were interested in education in medical ethics and looked upon ethical training as being an important part of their studies. Medical students are interested in ethical education during the clinical period of their studies, which has been taken into account since the actual change of the curriculum. Radio-oncologists as specialists in other clinical fields can offer important contributions when they discuss clinical cases from the viewpoint of medical ethics. The long-term effect of such an education will become the subject of future research.
Curriculum↗
[Cataract types in diabetics and non-diabetics: a densitometric study with the Topcon-Scheimpflug camera].
BACKGROUND: The purpose of this study was to compare types of cataract which appear in patients with the cataractogenous risk factor diabetes mellitus type II and in non-diabetics. MATERIALS AND METHODS: The opaque lenses of 46 diabetics (group I) and 83 non-diabetics (group II) in the age range of 55-93 years, who had to undergo a cataract operation, were documented using the Topcon-Scheimpflug camera SL-45 followed by densitometric analysis. RESULTS: Although there was no significant difference relating to the metabolic disorder, we found a higher percentage of opacity of the deeper anterior (I = 8.7 % II = 3.6 %) as well as in the anterior and posterior cortex (I = 13.0 % II = 8.4 %) comparing diabetics and non-diabetics. CONCLUSION: Diabetics revealed a higher percentage of opacity of the area of the cortex than non-diabetics without detecting any significance. Thereby, we could show positive associations between the existence of diabetes mellitus type II and a higher risk of opacities of the cortex.
Aged↗
Parathyroid hormone-related peptide improves contractile responsiveness of adult rat cardiomyocytes with depressed cell function irrespectively of oxidative inhibition.
Parathyroid hormone-related peptide (PTHrP) was found to improve contractile function of stunned myocardium in pigs. The peptide is released from coronary endothelial cells during ischemia and significantly improves post-ischemic recovery. The present study was aimed to decide whether such an induction of contractile responsiveness of the heart requires co-activation of adjacent cells or is a genuine phenomenon of cardiomyocytes. A second aim of this study was to decide whether such an improvement is linked to depressed cell function in general or oxidative inhibition. Isolated adult ventricular cardiomyocytes from rats were constantly paced at 0.5 Hz for 10 min. Cells were exposed to a brief oxidative inhibition by addition of 0.5 mmol/l potassium cyanide (KCN) in the presence of glucose. Under these conditions, cells stopped beating after 280 s on average. 30 s before they stopped to beat, cells had already developed a reduction in cell shortening, maximal relaxation and contraction velocity. In the co-presence of PTHrP (1-34) (100 nmol/l) cells continued to beat regular and did not develop reduced cell shortening, irrespectively of oxidative inhibition. In a second attempt, cells were exposed to the NO donor SNAP (100 micromol/l) or 8-bromocGMP (1 mmol/l). As expected both agents reduced cell shortening significantly. This reduction in cell shortening was attenuated in co-presence of PTHrP, too. Finally, we investigated the effect of PTHrP on cell shortening at different extracellular concentrations of calcium. Although, PTHrP increased intracellular calcium at 2 and 5 mmol/l extracellular calcium, respectively, it improved cell shortening only at 5 mmol/l extracellular calcium. Thus, the beneficial effect of PTHrP on cell shortening was independent from intracellular calcium but dependent on the steepness of the calcium gradient between intra- and extracellular calcium. In conclusion, our study shows that PTHrP is able to improve cell shortening rapidly and directly irrespectively of the reason for the reduced cell function. Improved electromechanical coupling rather than intracellular calcium handling seems to be the most important mechanism.
Animals↗
Mechanism of cGMP-mediated protection in a cellular model of myocardial reperfusion injury.
OBJECTIVE: Reperfusion injury of the myocardium is characterised by development of cardiomyocyte hypercontracture. Previous studies have shown that cGMP-mediated stimuli protect against reperfusion injury, but the cellular mechanism is still unknown. METHODS: To simulate ischemia/reperfusion, adult rat cardiomyocytes were incubated anoxically (pH(o) 6.4) and then reoxygenated (pH(o) 7.4). Cytosolic calcium [Ca(2+)](i) (fura-2 ratio), pH(i) (BCECF ratio), cell length, and phospholamban phosphorylation were analysed. Under simulated ischemia cardiomyocytes develop [Ca(2+)](i) overload. When reoxygenated they rapidly undergo hypercontracture, triggered by oscillations of [Ca(2+)](i). We investigated whether cGMP-mediated stimuli can modulate [Ca(2+)](i) or pH(i) recovery and whether this contributes to their protective effect. Membrane-permeable cGMP analogues, 8-bromo-cGMP (1 mmol/L) or 8-pCPT-cGMP (10 micrommol/L), or a receptor-mediated activator of particulate guanylyl cyclase, urodilatin (1 micromol/L), were applied. RESULTS: The investigated stimuli protect against reoxygenation-induced hypercontracture (cell length as percent of end-ischemic length; control: 68+/-1.6; 8-bromo-cGMP: 88+/-1.5*; 8-pCPT-cGMP: 84+/-2.9*; urodilatin: 87+/-1.1*; n=24; *p<0.05). Recovery from [Ca(2+)](i) overload after 2 min reoxygenation [fura-2 ratio (a.u.); control: 1.43+/-0.15; 8-bromo-cGMP: 1.86+/-0.15*; 8-pCPT-cGMP: 1.92+/-0.19*; urodilatin: 1.93+/-0.24*; n=25; *p<0.05] was accelerated, and the frequency of [Ca(2+)](i) oscillations (min(-1)) was significantly reduced (control: 49+/-5.0 min(-1); 8-bromo-cGMP: 18+/-3.5* min(-1); 8-pCPT-cGMP: 18+/-4.5* min(-1); urodilatin: 16+/-4.1* min(-1); n=24; *p<0.05). cGMP-mediated stimuli increased sarcoplasmic Ca(2+) sequestration (caffeine-releasable Ca(2+) pool: 2-3 fold increase vs. control). Inhibition of sarcoplasmic Ca(2+)-ATPase (SERCA) by thapsigargin (150 nmol/L) or of protein kinase G with KT-5823 (1 micromol/L) abolished the effect of these stimuli on [Ca(2+)](i) recovery. The investigated stimuli significantly enhanced phospholamban phosphorylation. CONCLUSIONS: We conclude that cGMP-dependent signals activate SERCA via a protein kinase G-dependent phosphorylation of phospholamban. The increase in SERCA activity seems to reduce peak [Ca(2+)](i) and [Ca(2+)](i) oscillation during reoxygenation and to attenuate the excessive activation of the contractile machinery that otherwise leads to the development of hypercontracture.
Animals↗
[Waiting lists in German radio-oncology. Egalitarian justice and evidence based medicine can be used as an aid for allocation of scarce resources].
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Evidence-Based Medicine↗
JAK and STAT proteins are expressed and activated by IFN-gamma in rat pancreatic acinar cells.
The development of acute pancreatitis (AP) is triggered by acinar events, but the subsequent extra-acinar events, particularly a distinct immune response, appear to determine its severity. Cytokines modulate this immune response and are derived not only from immunocytes but also from pancreatic acinar cells. We studied whether pancreatic acinar cells were also capable of responding to cytokines. The JAK/STAT-pathway represents the main effector for many cytokines. Therefore, expression and regulation of JAK and STAT proteins were investigated in rat pancreatic acinar cells. Western blotting showed expression of JAK1, JAK2, Tyk2, and STAT1, STAT2, STAT3, STAT5, STAT6. In addition, STAT1 was reversibly tyrosine-phosphorylated upon the procedure of acinar cell isolation. In contrast, STAT3-phosphorylation occurred spontaneously after pancreas removal and was not reversible within 8 h. STAT1 phosphorylation was also observed upon treatment with IFN-gamma but not upon EGF, TNF-alpha or IL-6, and inhibited by the JAK2-inhibitor AG-490. Immunohistochemistry revealed cytoplasmic expression of unphosphorylated STAT1 in untreated acinar cells and nuclear translocation of phosphorylated STAT1 following IFN-gamma-treatment. Interestingly, although CCK leads to the activation of multiple stress pathways in pancreatic acinar cells, we found no influence of CCK on phosphorylation of STAT1, STAT3, or STAT5 in the pancreas. In conclusion, our data provide further evidence that pancreatic acinar cells are able to interact with immune cells. Besides stimulating immune cells via cytokine secretion, acinar cells are in turn capable of responding to IFN-gamma via JAK2 and STAT1 which may have an impact on the development of AP.
Animals↗
[KIS-RIS-PACS integration: the Marburg approach].
When describing the development of data processing at the Department of Radiology at the Philipps University of Marburg, three phases can be identified covering the areas of patient care, education, and research as well as administrative and organizational aspects. The first phase (1987-1995) was centered on radiology and characterized by the early implementation of the radiology information system (RIS) and installation of a picture archiving and communication system (PACS). The experiences gained during this phase led to intensive discussion on application-oriented information processing. The second phase (1996-2000) describes the changes in the general framework brought by Internet technology and international standards. The course was set for the future of data processing in the hospital setting. The phase ended with implementation of a clinical workplace system (KAS) as the basis for a comprehensive electronic patient record and the switch in radiology to an integrated RIS solution. The third phase (2001-2006) addressed further implementation and development of clinical data management in which both regular documentation of patient data and information processing not related to patients are optimized by making use of Intranet/Internet technology. It includes the hospital wide implementation of PACS and the forthcoming phase of information processing increasingly shaped by workflow and decision support.
Database Management Systems↗
Enhanced blood coagulation and fibrinolysis in mice lacking histidine-rich glycoprotein (HRG).
Histidine-rich glycoprotein (HRG) is a serum protein belonging to the cystatin superfamily. HRG may play a regulatory role in hemostasis and innate immunity. However, this role is uncertain because of a lack of rigorous testing in an animal model. We generated mice lacking the translation start point of exon 1 of the Hrg gene, effectively resulting in a null mutation (Hrg-/-). The mice were viable and fertile but had no HRG in their blood. Antithrombin activity in the plasma of Hrg-/- mice was higher than in the plasma of heterozygous Hrg+/- or wild-type Hrg+/+ mice. The prothrombin time was shorter in Hrg-/- mice than in Hrg+/- and Hrg+/+ mice. Bleeding time after tail tip amputation in Hrg-/- mice was shorter than in Hrg+/+ mice. The spontaneous fibrinolytic activity in clotted blood of Hrg-/- mice was higher than in Hrg+/+ mice. These findings suggest that HRG plays a role as both an anticoagulant and an antifibrinolytic modifier, and may regulate platelet function in vivo.
Animals↗
Large-scale homogeneous molecular templates for femtosecond time-resolved studies of the guest-host interaction.
Self-assembled monolayer films based on iodobenzoyloxy-functionalized resorc[4]arenes were prepared on gold substrates to serve as model systems for future time-resolved studies of molecular recognition, a mechanism of outstanding importance in bioorganic systems. The film properties were tested using X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM) and imaging ellipsometry. An apparatus for time-resolved electron spectroscopy utilizing femtosecond soft X-ray pulses is capable of detecting iodine core-level photolines and the photoinduced dissociation after ultraviolet illumination. The developed technique holds promise for tracking the temporal evolution of chemical shifts of atomic markers as local probes for the dynamics of the guest-host interaction.
Benzoates↗
The first minutes of reperfusion: a window of opportunity for cardioprotection.
During the past decade, the understanding has grown that control of the conditions of reperfusion is critical for salvaging ischemic-reperfused myocardium. The first few minutes of reperfusion constitute a critical phase, as here lethal tissue injury in addition to that already developed during ischemia may be initiated. The identification of the mechanisms of reperfusion-induced cell death opens a new window of opportunity for cardioprotection in the clinic. Development of cardiomyocyte hypercontracture is a predominant feature of reperfusion injury. We and others have shown that control of hypercontracture in reperfusion reduces the extent of tissue injury. On the cellular level, it was shown that reperfusion-induced hypercontracture might either originate from a rigor-type mechanism, when energy recovery proceeds very slowly, or from Ca2+ overload, when energy recovery is rapid but cytosolic Ca2+ load is high. These two mechanisms can be influenced by various interventions that either connect with cytosolic Ca2+ control or myofibrillar Ca2+ sensitivity or with mitochondrial energy production. These experimental approaches will hopefully lead to novel strategies for clinical cardioprotection during the early phase of reperfusion.
Calcium↗
Intracellular calcium: a prerequisite for aldosterone action.
Transport of salt and water in various tissues is under control of the mineralocorticoid hormone aldosterone. As a liphophilic hormone, aldosterone diffuses through the plasma membrane and, then, binds to cytosolic mineralocorticoid receptors in the target cells. After binding to nuclear pore complexes, the activated receptor is translocated to the nucleus where transcription processes are initiated. After a lag period of about 20 minutes hormone-specific early mRNA transcripts leave the nucleus through nuclear pores. Some of the steps in this cascade can be followed by electrophysiology in Xenopus laevis oocyte nuclei. In addition to the genomic pathway, aldosterone exerts a rapid pre-genomic response that involves an increase in intracellular calcium. In this study, we tested for the potential role of Ca(2+) in the genomic response of the hormone. We measured the electrical resistance across the nuclear envelope in response to aldosterone, in presence and absence of intracellular Ca(2+). Nuclear envelope electrical resistance reflects receptor binding to the nuclear pore complexes ("early" resistance peak, 2 minutes after aldosterone), ongoing transcription ("transient" resistance drop, 5-15 minutes after aldosterone) and mRNA export ("late" resistance peak, 20 minutes after aldosterone). Pre-injection of the Ca(2+) chelator EGTA eliminated all electrical responses evoked by aldosterone. The transient resistance drop and the late resistance peak, induced by the hormone, were prevented by the transcription inhibitor actinomycin D, coinjected with aldosterone, while the early resistance peak remained unaffected. We conclude that (i). the presence of intracellular Ca(2+) is a prerequisite for the genomic action of aldosterone. (ii). Intracellular calcium plays a role early in the signaling cascade, either in agonist-receptor interaction, or receptor transport/docking to the nuclear pore complexes.
Aldosterone↗
Endothelial cell swelling by aldosterone.
There is accumulating evidence that mineralocorticoids not only act on kidney but also on the cardiovascular system. We investigated the response of human umbilical venous endothelial cells (HUVECs) to aldosterone at a time scale of 20 minutes in absence and presence of the aldosterone antagonist spironolactone or other transport inhibitors. We applied atomic force microscopy (AFM), which measures cell volume and volume shifts between cytosol and cell nucleus. We observed an immediate cell volume increase (about 10%) approximately 1 min after addition of aldosterone (0.1 micromol/l), approaching a maximum (about 18%) 10 min after aldosterone treatment. Cell volume returned to normal 20 min after hormone exposure. Spironolactone (1 micromol/l) or amiloride (1 micromol/l) prevented the late aldosterone-induced volume changes but not the immediate change observed 1 min after hormone exposure. AFM revealed nuclear swelling 5 min after aldosterone addition, followed by nuclear shrinkage 15 min later. The Na(+)/H(+) exchange blocker cariporide (10 micromol/l) was ineffective. We conclude: (i). Aldosterone induces immediate (1 min) swelling independently of plasma membrane Na(+) channels and intracellular mineralocorticoid receptors followed by late mineralocorticoid receptor- and Na(+)-channel-dependent swelling. (ii). Intracellular macromolecule shifts cause the changes in cell volume. (iii). Both amiloride and spironolactone may be useful for medical applications to prevent aldosterone-induced vasculopathies.
Adaptation, Physiological↗
[Decision aid for cancer in pregnancy. An introduction to casuistic bioethics].
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Abortion, Induced↗
Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia.
Endothelial cells exhibit an autonomous proliferative response to hypoxia, independent of paracrine effectors. In cultured endothelial cells of porcine aorta, we analyzed the signaling of this response, with a focus on the roles of redox signaling and the MEK/ERK pathway. Transient hypoxia (1 hour) stimulated proliferation by 61+/-4% (n=16; P<0.05 versus control), quantified after 24 hours normoxic postincubation. Hypoxia induced an activation of ERK2 and of NAD(P)H oxidase and a burst of reactive oxygen species (ROS), determined by DCF fluorescence. To inhibit the MEK/ERK pathway, we used PD 98059 (PD, 20 micromol/L); to downregulate NAD(P)H oxidase, we applied p22phox antisense oligonucleotides; and to inhibit mitochondrial ROS generation, we used the ubiquinone derivate mitoQ (MQ, 10 micromol/L). All three inhibitions suppressed the proliferative response: PD inhibited NAD(P)H oxidase activation; p22phox antisense transfection did not inhibit ERK2 activation, but suppressed ROS production; and MQ inhibited ERK2 activation and ROS production. The autonomous proliferative response depends on the MEK/ERK pathway and redox signaling steps upstream and downstream of ERK. Located upstream is ROS generation by mitochondria, downstream is NAD(P)H oxidase.
Animals↗
Inhibition of contractile activation reduces reoxygenation-induced endothelial gap formation.
OBJECTIVE: Barrier function of coronary endothelium becomes disturbed by ischemia-reperfusion. We investigated the mechanism of reperfusion-induced endothelial gap formation in monolayers of cultured endothelial cells (CEC) of the rat, exposed to simulated ischemia (40 min anoxia, pH(o) 6.4) and reperfusion (30 min reoxygenation, pH(o) 7.4). METHODS: Cytosolic Ca(2+) (fura-2) and intercellular gap formation (planimetrical analysis) were determined. Reoxygenation conditions were varied: (a) continuing perfusion at pH(o) 6.4, (b) with or without glucose (2.5 mM), (c) in presence of NaCN (2 mM), (d) with Ca(2+) (10 mM) or BAPTA/AM (25 microM), (e) in the presence of myosin light chain kinase inhibitors ML-7 (5 microM) or wortmannin (1 microM). RESULTS: During anoxia, CEC developed cytosolic Ca(2+) overload which was not reversed during 30 min reoxygenation. Intercellular gap formation started during anoxia, but was increased during reoxygenation. Reoxygenation-related gap formation was largest in presence of glucose, lower when glucose was withdrawn or NaCN was added. Presence of ML-7 or wortmannin also reduced gap formation during reoxygenation. CONCLUSIONS: Reoxygenation induces gap formation. This is dependent on (i) Ca(2+) overload during reoxygenation, (ii) energy production and (iii) activation of myosin light chain kinase. Together these results indicate that activation of the endothelial contractile machinery is the underlying cause.
Androstadienes↗
Signaling of hypoxia-induced autonomous proliferation of endothelial cells.
Endothelial cells exhibit an autonomous proliferative response to hypoxia, independent of paracrine effectors. In cultured endothelial cells of porcine aorta, we analyzed the signaling and compared hypoxia with mitochondrial inhibition by rotenone. Particularly, roles of the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway and cytosolic Ca2+ were studied. Hypoxia resulted in increased proliferation by 65+/-2%. Hypoxia induced transient activation of p42 MAPK (phosphorylation rose from 11+/-5 to 51+/-7%), followed by translocation of p42 MAPK into the nucleus. The proliferative response was diminished after inhibition of the MEK/MAPK pathway by PD 98059 (20 microM) or UO 126 (10 microM) but not sensitive to 8-phenyl-theophillin (10 microM), an adenosine receptor blocker, nor to a neutralizing antibody for vascular endothelial growth factor (VEGF). Inhibition of intracellular Ca2+ release, capacitive Ca2+ influx, or removal of extracellular Ca2+ prevented hypoxic Ca2+ overload and the proliferative response. Suppression of cytosolic Ca2+ rise did not interfere with activation of p42 MAPK but abolished its nuclear translocation. Effects of hypoxia were mimicked by rotenone (10 microM. Transient hypoxic inhibition of mitochondria induces a proliferative endothelial response mediated through Ca2+-independent activation and Ca2+-dependent nuclear translocation of p42 MAPK. This proliferative response is independent of adenosine or VEGF.
Active Transport, Cell Nucleus↗