Search PubMed⌕ Search

Biomedical subjects

K Peter

Publications and source records attributed to K Peter.

At least 55 records · Page 3Linked to original sources
PubMed1999

Effects of mutations in the cytoplasmic domain of integrin beta(1) to talin binding and cell spreading.

Integrins are transmembrane proteins linking the extracellular matrix or certain cell-cell contacts to the cytoskeleton. To study integrin-cytoskeleton interactions we wanted to relate talin-integrin interaction to integrin function in cell spreading and formation of focal adhesions. For talin-binding studies we used fusion proteins of glutathione S-transferase and the cytoplasmic domain of integrin beta(1) (GST-cytobeta(1)) expressed in bacteria. For functional studies chimeric integrins containing the extracellular and transmembrane parts of beta(3) linked to the cytoplasmic domain of beta(1) were expressed in CHO cells as a dimer with the alpha(IIb) subunit. Point mutations in the amino acid sequence N(785)PIY(788) of beta(1) disrupted both the integrin-talin interaction and the ability of the integrin to mediate cell spreading. COOH-terminal truncation of beta(1) at the amino acid position 797 disrupted its ability to mediate cell spreading, whereas the disruption of talin binding required deletion of five more amino acids (truncation at position 792). A synthetic peptide from this region of beta(1) (W(780)DTGENPIYKSAV(792)) bound to purified talin and inhibited talin binding to GST-cytobeta(1). The ability of the mutants to mediate focal adhesion formation or to codistribute to focal adhesions formed by other integrins correlated with their ability to mediate cell spreading. These results confirm the previous finding that a talin-binding site in the integrin beta(1) tail resides at or close to the central NPXY motif and suggest that the integrin-talin interaction is necessary but not sufficient for integrin-mediated cell spreading.

3T3 Cells↗
PubMed1999

Efficient endocytosis of the cystic fibrosis transmembrane conductance regulator requires a tyrosine-based signal.

We previously demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR) is rapidly endocytosed in epithelial cells (Prince, L. S., Workman, R. B., Jr., and Marchase, R. B. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 5192-5196). To determine the structural features of CFTR required for endocytosis, we prepared chimeric molecules consisting of the amino-terminal (residues 2-78) and carboxyl-terminal tail regions (residues 1391-1476) of CFTR, each fused to the transmembrane and extracellular domains of the transferrin receptor. Functional analysis of the CFTR-(2-78) and CFTR-(1391-1476) indicated that both chimeras were rapidly internalized. Deletion of residues 1440-1476 had no effect on chimera internalization. Mutations of potential internalization signals in both cytoplasmic domains reveal that only one mutation inhibits internalization, Y1424A. Using a surface biotinylation reaction, we also examined internalization rates of wild type and mutant CFTRs expressed in COS-7 cells. We found that both wild type and A1440X CFTR were rapidly internalized, whereas the Y1424A CFTR mutant, like the chimeric protein, had approximately 40% reduced internalization activity. Deletions in the amino-terminal tail region of CFTR resulted in defective trafficking of CFTR out of the endoplasmic reticulum to the cell surface, suggesting that an intact amino terminus is critical for biosynthesis. In summary, our results suggest that both tail regions of CFTR are sufficient to promote rapid internalization of a reporter molecule and that tyrosine 1424 is required for efficient CFTR endocytosis.

Amino Acid Sequence↗
PubMed1999

[In Process Citation]

Intensive care medicine for both surgical and medical patients has a common scientific and clinical basis. In critically ill patients the medical conditions are complex and can be managed only by specialists thoroughly trained in intensive care medicine. Therefore, surgeons as well as anesthesiologists must have a detailed theoretical and clinical knowledge of intensive care medicine. Surgical training places the emphasis on operative skills, while intraoperative management of the patient by the anesthesiologist calls for skills involved in intensive care medicine. Interdisciplinary cooperation between specialists is essential to improve the quality of intensive care medicine further. The cooperation that already exists between surgeons and anesthesiologists makes closer collaboration in the future a logical step.

Journal Article↗
PubMed1999

Comparison of five sedation scoring systems by means of auditory evoked potentials.

OBJECTIVE: To review five sedation scoring systems and to determine their correlation with an objective method for assessing the level of sedation by means of auditory evoked potentials (AEP) in critically ill patients. DESIGN: Prospective clinical study. SETTING: Multidisciplinary intensive care unit in a university hospital. PATIENTS: Ninety-five consecutive patients requiring sedation during intensive care therapy. MEASUREMENTS AND RESULTS: Previous studies have shown that auditory evoked potentials, especially latencies of the midlatency component N(b), could serve as an indicator of depth of anaesthesia. In the present study we used this electrophysiological method to evaluate sedation during intensive care therapy. Changes in latency of peak N(b) were compared with various levels of sedation assessed by five established sedation scoring systems. As in anaesthesia, latencies of N(b) increased with increasing depth of sedation. Among the scoring systems, the one developed by Ramsay correlated best with changes in N(b) latency (r2=0.68). The coefficient of determination, r2, of the other scores ranged from 0.56 to 0.61. CONCLUSION: For the assessment of sedation, several scoring systems have been introduced into clinical practice, but the differentiation of deeper sedation levels, especially, remains poor. In this study we compared auditory evoked potentials, as an objective method with which to assess the level of sedation, with five different sedation scoring systems. In comparison with changes in latency of the midlatency component N(b), Ramsay's sedation score showed the closest correlation. Objective electrophysiological monitoring is desirable during long-term sedation.

APACHE↗
PubMed1999

Effects of noninvasive positive pressure ventilatory support in non-COPD patients with acute respiratory insufficiency after early extubation.

OBJECTIVE: To investigate the effects of noninvasive positive pressure ventilation (NPPV) on pulmonary gas exchange, breathing pattern, intrapulmonary shunt fraction, oxygen consumption, and resting energy expenditure in patients with persistent acute respiratory failure but without chronic obstructive pulmonary disease (COPD) after early extubation. DESIGN: Prospective study. SETTING: Multidisciplinary intensive care unit of a university hospital. PATIENTS: 15 patients after prolonged mechanical ventilation (> 72 h) with acute respiratory insufficiency after early extubation. INTERVENTIONS: Criteria for early extubation were arterial oxygen tension (PaO2) > or = 40 mm Hg (fractional inspired oxygen 0.21), arterial carbon dioxide tension (PaCO2) < or = 55 mm Hg, pH > 7.32, respiratory rate < or = 40 breaths per min, tidal volume (VT) > or = 3 ml/kg, rapid shallow breathing index < or = 190 and negative inspiratory force > or = 20 cmH2O. After extubation, two modes of NPPV were applied [continuous positive airway pressure (CPAP) of 5 cmH2O and pressure support ventilation (PSV) with 15 cmH2O pressure support]. MEASUREMENTS AND MAIN RESULTS: Oxygenation and ventilatory parameters improved during both modes of NPPV (p < 0.05): increase in PaO2 of 11 mm Hg during CPAP and 21 mm Hg during PSV; decrease in intrapulmonary shunt fraction of 7% during CPAP and 12% during PSV; increase in tidal volume of 1 ml/kg during CPAP and 4 ml/kg during PSV; decrease in respiratory rate 6 breaths/min during CPAP and 9 breaths/min during PSV. Oxygen consumption (15% during CPAP, 22% during PSV) and resting energy expenditure (12% during CPAP, 20% during PSV) were reduced (p < 0.05). PaCO2 decreased, whereas minute ventilation and pH increased during PSV (p < 0.05). The median duration of NPPV was 2 days. Two patients had to be reintubated. CONCLUSIONS: In non-COPD patients with persistent acute respiratory failure after early extubation, NPPV improved pulmonary gas exchange and breathing pattern, decreased intrapulmonary shunt fraction, and reduced the work of breathing.

APACHE↗
PubMed1999

Checking for breathing: evaluation of the diagnostic capability of emergency medical services personnel, physicians, medical students, and medical laypersons.

STUDY OBJECTIVE: International guidelines for cardiopulmonary resuscitation (CPR) recommend determination of unconsciousness, breathlessness, and absence of pulse to diagnose cardiorespiratory arrest. Thus far, there have been no scientifically proven data available regarding the quality of assessing breathlessness. The study objective was to evaluate the effectiveness of checking for breathing in an emergency situation, to determine the necessary amount of time until diagnosis, and to document used techniques. METHODS: Four different populations were tested for their ability to assess breathlessness: emergency medical services (EMS) personnel, physicians, medical students, and laypersons. Each participant was asked to perform the diagnostic procedure twice, first with a breathing or not-breathing unresponsive test person and then with a modified megacode manikin (with the possibility of simulated respiratory function). The order of testing and the respiratory status were strictly randomized. Diagnostic accuracy, time interval to diagnosis, and used techniques were documented. RESULTS: A total of 261 persons were tested in 522 trials, with a median time interval of 12 seconds for obtaining a diagnosis. Regarding all participants, the correct diagnosis was achieved in 81.0% (EMS personnel, 89.7%; physicians, 84.5%; medical students, 78.4%; laypersons, 71.5%). Only 55.6% of all participants showed correct diagnostic skills (EMS personnel, 91.3%; physicians, 51.5%; medical students, 61.9%; laypersons, 18.5%). CONCLUSION: Checking for breathing was shown to be mostly inaccurate and unreliable. This diagnostic procedure takes more time than recommended in international guidelines. Therefore CPR training should focus more on the determination of breathlessness. Also, the guidelines for CPR should be revised.

Apnea↗
PubMed1999

[Life-long hemorrhagic diathesis in a young man with unclottable global coagulation tests--congenital afibrinogenemia].

Congenital afibrinogenemia is a rare autosomal recessive hemostatic disorder leading to unclottable global coagulation tests. Furthermore, it is associated with abnormal platelet aggregation and with severe bleeding episodes if untreated. Surprisingly, thrombotic complications may be observed quite frequently in afibrinogenemic patients following replacement of fibrinogen. A case of congenital afibrinogenemia is described in a patient who suffered from severe bleeding episodes in the absence of replacement therapy but developed a deep vein thrombosis with multiple pulmonary emboli after fibrinogen replacement and surgical treatment of a hip fracture, despite conventional heparin prophylaxis.

Adult↗
PubMed1999

The effect of intravenously administered magnesium on platelet function in patients after cardiac surgery.

UNLABELLED: After cardiac surgery, magnesium is often administered for prophylaxis and treatment of cardiac arrhythmias. Magnesium, however, inhibits platelet function in vitro and in healthy volunteers. We performed a randomized, blinded, and placebo-controlled study to investigate the effect of magnesium on platelet function in patients after cardiac surgery. We studied patients who underwent uneventful coronary revascularization with cardiopulmonary bypass on the first postoperative day. Before and after an infusion of either 5.4 mmol magnesium (n = 19) or saline (n = 20), platelet function was investigated by means of in vitro bleeding time, platelet aggregation, and flow-cytometric assays. In addition, to investigate platelet function in vitro, 1, 5, and 10 mM magnesium were added to platelet-rich plasma before and 24 h after surgery in 30 patients. Compared with the control group, magnesium prolonged the in vitro bleeding time (22%) and inhibited ADP- and collagen-induced platelet aggregation (13% and 17%), platelet P-selectin expression (18%), and the binding of fibrinogen to the platelet glycoprotein IIb/IIIa receptor (10%). Magnesium also led to significant dose-dependent inhibition of platelet aggregation (19%), P-selectin expression (14%), and fibrinogen binding (11%) before and after surgery in vitro. Although the antithrombotic effect of magnesium may be beneficial in patients after coronary revascularization, large-dose magnesium therapy should be carefully considered in patients with impaired platelet function and co-existing bleeding disorders. IMPLICATIONS: In a randomized, blinded, placebo-controlled study of patients 24 h after coronary artery bypass grafting, IV administered magnesium inhibited platelet function in vitro and in vivo.

Adenosine Diphosphate↗
PubMed1999

Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study.

OBJECTIVE: To investigate the effects of stress doses of hydrocortisone on the duration of vasopressor therapy in human septic shock. DESIGN: Prospective, randomized, double-blind, single-center study. SETTING: Twenty-bed multidisciplinary intensive care unit in a 1400-bed university hospital. PATIENTS: Forty consecutive patients who met the ACCP/SCCM criteria for septic shock. An additional criterion for inclusion in the study was vasopressor support and high-output circulatory failure with a cardiac index of >4 L/min/m2 after fluid resuscitation (pulmonary capillary wedge pressure: 12-15 mm Hg) and without the use of positive inotropes such as dobutamine or dopexamine. The primary study end point was the time to cessation of vasopressor support (norepinephrine or epinephrine in any dose, dopamine > or = 6 microg/kg/min). Secondary study end points were the evolution of hemodynamics and the multiple organ dysfunction syndrome (MODS). The severity of illness at recruitment was graded using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems. MODS was described by the Sepsis-related Organ Failure Assessment score. INTERVENTIONS: All eligible patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started with a loading dose of 100 mg given within 30 mins and followed by a continuous infusion of 0.18 mg/ kg/hr. When septic shock had been reversed, the dose of hydrocortisone was reduced to 0.08 mg/kg/hr. This dose was kept constant for 6 days. As soon as the underlying infection had been treated successfully or sodium serum concentrations had increased to >155 mmol/L, the hydrocortisone infusion was tapered in steps of 24 mg/day. Physiologic saline solution was the placebo. MEASUREMENTS AND MAIN RESULTS: Hemodynamic and oxygen-derived variables were measured at previously defined time points over a study period of 5 days. Relevant clinical and laboratory measurements were registered for a study period of 14 days to assess the evolution of organ dysfunction. Baseline data at recruitment did not differ between the two groups. Shock reversal was achieved in 18 of the 20 patients treated with hydrocortisone vs. 16 of the 20 patients treated with placebo. Hydrocortisone significantly reduced the time to cessation of vasopressor support. The median time of vasopressor support was 2 days (1st and 3rd Quartiles, 1 and 6 days) in the hydrocortisone-treated group and 7 days (1st and 3rd Quartiles, 3 and 19 days) in the placebo group (p = .005 Breslow test). There was a trend to earlier resolution of the organ dysfunction syndrome in the hydrocortisone group. CONCLUSIONS: Infusion of stress doses of hydrocortisone reduced the time to cessation of vasopressor therapy in human septic shock. This was associated with a trend to earlier resolution of sepsis-induced organ dysfunctions. Overall shock reversal and mortality were not significantly different between the groups in this low-sized single-center study.

Adult↗
PubMed1999

Recombinant human growth hormone for reconditioning of respiratory muscle after lung volume reduction surgery.

OBJECTIVE: To investigate the effects of recombinant human growth hormone (rHGH) as a "rescue treatment" in an end-stage chronic obstructive pulmonary disease patient after prolonged weaning failure. DESIGN: Descriptive case report. SETTING: Fifteen-bed intensive care unit in a university hospital. PATIENT: A 62-year-old man with end-stage chronic obstructive pulmonary disease and pulmonary emphysema after lung reduction surgery and prolonged weaning failure after long-term mechanical ventilation. INTERVENTIONS: After 42 days of unsuccessful weaning from the respirator, rHGH (27 IU/day, 0.3 IU/kg body weight/day) was administered for 20 days through a subcutaneous injection in addition to standard intensive care. MEASUREMENTS AND MAIN RESULTS: In addition to daily routine laboratory studies, the visceral proteins prealbumin, retinol-binding protein, and transferrin, and nitrogen balance were measured twice a week, as were the thyroid hormones triiodothyronine, thyroxine, and thyroid-stimulating hormone, plasma insulin levels, and the insulin-like growth factor (IGF)-1 binding proteins IGF-BP1 and IGF-BP3. IGF-1 was measured from day 1 to day 4 of rHGH administration. Nutritional support was guided by indirect calorimetry. Additionally, weaning variables such as peak expiratory flow rate and expiratory tidal volume were measured noninvasively. T-piece weaning trials were carried out daily until respiratory muscle fatigue occurred. IGF-1 increased in response to rHGH stimulation, from 103 to 230 microg/mL, within 4 days. The carrier protein IGF-BP3 increased from 126 to 283 mg/L at the end of the study period, and the inhibiting IGF-BP1 decreased initially from 19 to 14 mg/L and then increased until the end of the study to 31 mg/L. Nitrogen balance increased initially from 4.6 to 13.6 g/24 hrs and thereafter decreased until the end of rHGH treatment to 8.3 g/24 hrs. Resting energy expenditure increased from 1800 to 2300 kcal/24 hrs. Peak expiratory flow rate increased from 0.69 to 0.88 L/sec. The expiratory tidal volume showed a slight increase during the study period during the daily decrease of pressure support on the ventilator setting. Respiratory muscular strength increased beginning 10 days after rHGH therapy was started. From this point, T-piece weaning trials could be prolonged almost daily. The patient was extubated successfully on postoperative day 75. CONCLUSIONS: This case report shows that after a prolonged catabolic state and long-term mechanical ventilation, administration of rHGH not only enhances the response of protein metabolism but improves respiratory muscular strength. Therefore, it may reduce the duration of mechanical ventilation in selected patients.

Energy Metabolism↗
PubMed1999

A bispecific antifibrin-antiplatelet urokinase conjugate (BAAUC) induces enhanced clot lysis and inhibits platelet aggregation.

Thrombolysis is well established in the treatment of acute myocardial infarction. However, clinical application of thrombolytic agents has limitations with respect to efficacy and specificity. To achieve highly effective and at the same time clot-selective plasminogen activation urokinase was coupled to a bispecific antibody consisting of the monovalent Fab' from the antifibrin monoclonal antibody 59D8 and the monovalent Fab' from the anti-glycoprotein GPIIb/IIIa monoclonal antibody 7E3. The bispecific antifibrin-antiplatelet urokinase conjugate (BAAUC) was synthesized and characterized. Assays with either immobilized platelets, GPIIb/IIIa or fibrin showed an increase in plasminogen activation compared to uncoupled urokinase by 10-fold, 58-fold and 13-fold, respectivley (p < 0.0001 each). In vitro clot lysis was performed on platelet-rich and fibrin-rich clots and revealed an up to 5-fold higher potency of BAAUC compared to uncoupled urokinase (p < 0.0001). In vitro platelet aggregation was effectively inhibited by the hybrid molecule, whereas urokinase had no effect. BAAUC and two monospecific urokinase-conjugates, UK-59D8-IgG and UK-7E3-(Fab')2 were compared with each other with regard to similar tests. In vitro clot assays with platelet-rich and platelet-poor clots were performed. BAAUC achieved a significantly higher plasminogen activation compared to each of the monospecific conjugates (p < 0.05, respectively). We conclude that BAAUC, a bispecific plasminogen activator with antifibrin and antiplatelet properties has the potency to lyse both fibrin-rich and platelet-rich thrombi with high efficacy and to effectively inhibit platelet aggregation.

Antibodies, Bispecific↗
PubMed1999

[Initial manifestation of a manic syndrome in advanced age in subcortical arteriosclerotic encephalopathy (Binswanger disease)].

We describe the case of a 65-year old man who presented with a first episode of mania lacking a history of previous affective illness. Clinical, neuropsychological and NMR-findings pointed to a subcortical arteriosclerotic encephalopathy (Morbus Binswanger) as an underlying organic condition. According Kleman's concept of "secondary mania" this case illustrates the necessity a thorough search for organic conditions in late manifesting affective illness which may also involve therapeutic considerations.

Aged↗
PubMed1999

Plasminogen activator inhibitor type-1 (PAI-1) and its role in cardiovascular disease.

Cardiovascular disease is responsible for approximately 50% of total mortality in Europe, the USA and Japan. Established risk factors including smoking, hypercholesterolemia, and hypertension explain about half of the incidence of cardiovascular disease only. Reduced endogenous fibrinolytic activity secondary to increased plasma activity of plasminogen activator inhibitor type-1 (PAI-1) is now considered as a new cardiovascular risk factor. In this review, evidence is gathered for the notion that PAI-1 constitutes a predictor of cardiovascular disease and also contributes to the development of cardiovascular disease as a pathogenetic factor. The review will focus on experimental studies modulating PAI-1 activity and clinical studies addressing coronary heart disease, myocardial infarction, restenosis after coronary angioplasty, and graft occlusion after coronary artery bypass grafting.

Animals↗
PubMed1999

Oxidative stress and atherosclerosis: its relationship to growth factors, thrombus formation and therapeutic approaches.

The initiating event of atherogenesis is thought to be an injury to the vessel wall resulting in endothelial dysfunction. This is followed by key features of atherosclerotic plaque formation such as inflammatory responses, cell proliferation and remodeling of the vasculature, finally leading to vascular lesion formation, plaque rupture, thrombosis and tissue infarction. A causative relationship exists between these events and oxidative stress in the vessel wall. Besides leukocytes, vascular cells are a potent source of oxygen-derived free radicals. Oxidants exert mitogenic effects that are partially mediated through generation of growth factors. Mitogens, on the other hand, are potent stimulators of oxidant generation, indicating a putative self-perpetuating mechanism of atherogenesis. Oxidants influence the balance of the coagulation system towards platelet aggregation and thrombus formation. Therapeutic approaches by means of antioxidants are promising in both experimental and clinical designs. However, additional clinical trials are necessary to assess the role of antioxidants in cardiovascular disease.

Animals↗
PubMed1999

Soluble vascular cell adhesion molecule-1 (VCAM-1) as potential marker of atherosclerosis.

An increasing number of descriptive reports on soluble adhesion molecules and association with various diseases are published. Throughout these reports soluble adhesion molecules are identified as markers of inflammation. Since atherosclerosis demonstrates features of a chronic inflammatory disease, a potential association of soluble adhesion molecules with atherosclerosis has been postulated. However, conflicting results have been reported. One reason for this might be the differing definitions of atherosclerosis and patient groups. Besides the definition of atherosclerosis based on clinical symptoms, few reports use a direct quantification of atherosclerosis in their search for a marker of atherosclerosis. In those reports that quantify atherosclerosis, sVCAM-1 seems to be more specific for atherosclerosis than other markers. The serum level of sVCAM-1 appears to correlate with the extent of atherosclerosis and might allow for the detection of early stages of atherosclerosis. Large scale prospective studies will have to prove that sVCAM-1 can be used as a diagnostic tool for the detection of early stages of asymptomatic atherosclerosis and whether an early therapeutic intervention based on this approach is able to prevent progression and manifestation of the clinical sequelae of atherosclerosis.

Animals↗
PubMed1998

Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (alphaIIbbeta3) inhibitors.

The blockade of platelet integrin glycoprotein (GP) IIb/IIIa is a promising new antiplatelet strategy. The binding of ligands or of the ligand-mimetic peptide RGD causes a conformational change of GP IIb/IIIa from the nonactivated to the activated state. Because several blocking agents/inhibitors are ligand-mimetics, the current study evaluates whether these agents have the intrinsic property to activate GP IIb/IIIa. Fibrinogen binding to GP IIb/IIIa on platelets or on CHO cells expressing recombinant GP IIb/IIIa was evaluated by flow cytometry or 125I-labeled fibrinogen. Incubation with the monoclonal antibody (MoAb) fragment c7E3 (abciximab) results in fibrinogen binding to GP IIb/IIIa and in the access of ligand-induced binding sites. At low concentrations (0.01 to 0.1 microgram/mL), this intrinsic activating property of c7E3 can result in platelet aggregation. The disintegrin flavorodin and the RGD analogue fradafiban also induce fibrinogen binding, whereas the blocking MoAbs 2G12 and P2 and the activation-specific MoAb PAC-1 do not. Aspirin and indomethacin cannot block c7E3-induced fibrinogen binding to GP IIb/IIIa, but can inhibit c7E3-induced platelet aggregation. Thus, we conclude that GP IIb/IIIa inhibitors can demonstrate an intrinsic activating property, which can result in fibrinogen binding to GP IIb/IIIa and consequently in platelet aggregation. Cyclooxygenase inhibitors can inhibit platelet aggregation caused by GP IIb/IIIa inhibitors. Further studies will have to evaluate the clinical relevance of the potential intrinsic activating property of GP IIb/IIIa inhibitors and define consequences for the future drug development and evaluation of these potent antiplatelet agents.

Abciximab↗