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Biomedical subjects

K Peter

Publications and source records attributed to K Peter.

At least 19 recordsLinked to original sources
PubMed2006

Superparamagnetic iron oxide binding and uptake as imaged by magnetic resonance is mediated by the integrin receptor Mac-1 (CD11b/CD18): implications on imaging of atherosclerotic plaques.

INTRODUCTION: Superparamagnetic iron oxide nanoparticles (SPIONs) have been successfully used for magnetic resonance imaging (MRI) of atherosclerotic plaques. Endocytosis into monocytes/macrophages has been proposed as the mechanism for SPION uptake, but a specific receptor has not been identified yet. A potential candidate is the versatile integrin Mac-1 (CD11b/CD18, alphaMbeta2), which is involved in leukocyte adhesion, complement activation and phagocytosis. METHODS AND RESULTS: Intracellular SPION-accumulation was confirmed in cultured human monocytes using immunohistochemistry and iron staining. Recombinant cells expressing Mac-1 in different activation states as well as human monocytes with or without PMA stimulation were incubated either with an unspecific IgG or a CD11b-blocking antibody. Thereafter, cells were incubated with FITC-labeled amino-covered SPIONs or ferumoxtran-10 SPIONs and signal intensity was quantified by flow cytometry. Depending on the activation status of Mac-1, a significant increase in SPION binding/uptake was observed, independent on surface coating. Furthermore, SPION binding/uptake was significantly reduced after CD11b blockade. Results were confirmed in recombinant cells incubated with amino-PVA SPIONs and ferumoxtran-10, using T2(*)-weighted 3T MRI. CONCLUSION: The integrin Mac-1 is directly involved in SPION binding/uptake. Thus, monocytes abundantly expressing Mac-1 and especially activated monocytes expressing activated Mac-1 may be useful vehicles for high resolution MRI labeling of atherosclerotic plaques.

Animals↗
PubMed2006

Evidence for a differential functional regulation of the two beta(3)-integrins alpha(V)beta(3) and alpha(IIb)beta(3).

The functional regulation of integrins is a major determinant of cell adhesion, migration and tissue maintenance. The binding of cytoskeletal proteins to various sites of integrin cytoplasmic domains is a key mechanism of this functional regulation. Expression of recombinant integrin alpha(IIb)beta(3) and alpha(M)beta(2) lacking the GFFKR-region in CHO cells results in constitutively activated integrins. In contrast, CHO cells stably expressing either a GFFKR-deleted alpha(V(del))beta(3) or a FF to AA-substituted alpha(V(AA))beta(3) do not reveal a constitutively activated integrin. Adhesion to immobilized fibrinogen is strongly impaired in alpha(V(del))beta(3) or alpha(V(AA))beta(3)-expressing cells, whereas it is not impaired in alpha(IIb)beta(3) and alpha(M)beta(2), both lacking the GFFKR-region. In a parallel plate flow chamber assay, alpha(V)beta(3)-expressing cells adhere firmly to fibrinogen and spread even at shear rates of 15 to 20 dyn/cm(2), whereas alpha(V(del))beta(3) or alpha(V(AA))beta(3) cells are detached at 15 dyn/cm(2). Actin stress fiber formation and focal adhesion plaques containing alpha(V)beta(3) are observed in alpha(V)beta(3) cells but not in alpha(V(del))beta(3) or alpha(V(AA))beta(3)-expressing cells. As an additional manifestation of impaired outside-in signaling, phosphorylation of pp125(FAK) was reduced in these cells. In summary, we report that the GFFKR-region of the alpha(V)-cytoplasmic domain and in particular two phenylalanines are essential for integrin alpha(V)beta(3) function, especially for outside-in signaling. Our results suggest that the two beta(3)-integrins alpha(IIb)beta(3) and alpha(V)beta(3) are differentially regulated via their GFFKR-region.

Animals↗
PubMed2005

Dynamics of complex formation between biological and luminescent conjugated polyelectrolytes--a surface plasmon resonance study.

A water-soluble polythiophene, POWT, with zwitterionic peptide like side chains possess good characteristics for biosensor applications. The zwitterionic side chains of the polymer can couple to biomolecules via electrostatic and hydrogen bonding. This creates possibilities to imprint biomolecules to spin-coated polymer films with maintained functionality, and use the resulting matrix as a biosensor. Polymer-biomolecular interaction studies done with surface plasmon resonance (SPR) reveal a well performing sensor matrix with high affinity for DNA hybridizations as well as for protein detection. The responses are distinct and very specific. A directional dependence of antibodies binding to POWT layer has also been observed. The polymer films have also been characterized by optical methods. Emission and absorption measurements in different buffer systems confirm that the polymer matrix can undergo structural and conformational changes on surfaces. The dielectric function in the interval 300-800 nm of POWT is reported, based on variable angle spectroscopic ellipsometry. This modeling reveals that a considerable amount of water is included in the material. The polymer layer possesses the characteristics needed for biochip applications and micro array techniques.

Biocompatible Materials↗
PubMed2005

Inhibition of platelet activation and aggregation.

It has recently been established that platelets are involved at all stages of atherosclerotic disease. A major platelet mediated process is the acute vessel closure at the site of atherosclerotic plaque rupture and there is emerging evidence for platelet adhesion to endothelial cells in the early stage of atherosclerotic disease. This, through engagement of other cells, leads to the development of the atherosclerotic plaque. Beside dietary, cholesterol- and lipid-lowering, and other pharmaceutical approaches antiplatelet therapy plays an important part in the treatment of atherosclerosis and its multifarious clinical manifestations. Antiplatelet therapy and the currently approved substances for oral (acetylsalicylic acid, dipyridamole, cilostazol, ticlopidin and clopidogrel) and parenteral (acetylsalicylic acid, abciximab, eptifibatide and tirofiban) administration are discussed in the following section. Attention is given to each single agent and its mechanism of action. Differences in pharmacodynamic and pharmacokinetic properties are elucidated and outlook on future antiplatelet strategies is discussed.

Animals↗
PubMed2004

Effects of Pringle manoeuvre and ischaemic preconditioning on haemodynamic stability in patients undergoing elective hepatectomy: a randomized trial.

BACKGROUND: The Pringle manoeuvre and ischaemic preconditioning are applied to prevent blood loss and ischaemia-reperfusion injury, respectively, during liver surgery. In this prospective clinical trial we report on the intraoperative haemodynamic effects of the Pringle manoeuvre alone or in combination with ischaemic preconditioning. METHODS: Patients (n=68) were assigned randomly to three groups: (i) resection with the Pringle manoeuvre; (ii) with ischaemic preconditioning before the Pringle manoeuvre for resection; (iii) without pedicle clamping. RESULTS: Following the Pringle manoeuvre the mean arterial pressure increased transiently, but significantly decreased after unclamping as a result of peripheral vasodilation. Ischaemic preconditioning improved cardiovascular stability by lowering the need for catecholamines after liver reperfusion without affecting the blood sparing benefits of the Pringle manoeuvre. In addition, ischaemic preconditioning protected against reperfusion-induced tissue injury. CONCLUSIONS: Ischaemic preconditioning provides both better intraoperative haemodynamic stability and anti-ischaemic effects thereby allowing us to take full advantage of blood loss reduction by the Pringle manoeuvre.

Adult↗
PubMed2004

[The Stewart model. "Modern" approach to the interpretation of the acid-base metabolism].

About twenty years ago, Peter Stewart had already published his modern quantitative approach to acid-base chemistry. According to his interpretations, the traditional concepts of the mechanisms behind the changes in acid-base balance are considerably questionable. The main physicochemical principle which must be accomplished in body fluids, is the rule of electroneutrality. There are 3 components in biological fluids which are subject to this principle: a)Water, which is only in minor parts dissociated into H+ and OH-, b)"strong", i.e. completely dissociated, electrolytes, which thus do not interact with other substances, and body substances, such as lactate, and c)"weak", i.e. incompletely dissociated, substances. Peter Stewart strictly distinguished between dependent and independent variables and thus indeed described a new order of acid-base chemistry. The 3 dependent variables (bicarbonate concentration [Bic(-)], pH, and with this also hydrogen ion concentration [H(+)]) can only change if the 3 independent variables allow this change. These 3 independent variables are: 1. Carbon dioxide partial pressure, 2.the total amount of all weak acids ([A-] (Stewart called these ATOT), and 3.strong ion difference (SID). [A(-)] can be calculated from the albumin (Alb) and the phosphate concentration (Pi): [A(-)]=[Alb x (0.123 x pH - 0.631)] + [Pi x (0.309 x pH - 0.469)]. An apparent SID (or "bedside" SID) can be calculated using measurable ion concentrations: SID=[Na(+)] + [K(+)] - [Cl(-)]-lactate. Regarding the metabolic disturbances of acid-base chemistry, according to Stewart's terminology, changes in pH, [H(+)], and [Bic(-)] are only possible if either SID or [A(-)] itself changes. If, for example, SID decreases (e.g. in case of hyperchloremia), this increase in independent negative charges leads to a decrease in dependent negative charges in terms of [Bic(-)] resulting in acidosis (and vice versa). Therefore, according to Stewart, the decrease in SID during hyperchloremic acidosis results from the increase in serum chloride concentration and is the causal mechanism behind this acidosis. Contrary for example, a decrease in [A(-)] (e. g. during hypoalbuminemia) leads to an increase in [Bic(-)] and therefore to an alcalosis (and vice versa). Thus, by Stewart's approach, completely new acid-base disturbances, like "hyperchloremic acidosis" or "hypoalbuminemic alcalosis" (which, of course, can also exist in combination) can be detected, which had been unrecognised by the classic acid-base concepts. Consequently, Stewart's analysis can lead to a better understanding of the mechanisms behind the changes in acid-base balance.

Acid-Base Equilibrium↗
PubMed2004

Construction and characterization of a recombinant plasminogen activator composed of an anti-fibrin single-chain antibody and low-molecular-weight urokinase.

BACKGROUND: Targeting of plasminogen activators to the fibrin component of a thrombus by antibodies directed against human fibrin can enhance their thrombolytic potency and clot specificity. OBJECTIVES: To overcome the disadvantages of chemical conjugation, we investigated whether the recombinant fusion of a single-chain antibody and a plasminogen activator results in an active bifunctional molecule that might be useful as a therapeutic agent. METHODS: The cDNA of low-molecular-weight single-chain urokinase-type plasminogen activator, comprising amino acids Leu144-Leu411 (scuPA(LMW)), was cloned from human endothelial cells and fused to a single-chain antibody specific for the 7 N-terminal amino acids (beta(15-22)) in the beta-chain of human fibrin (scFv(59D8)). The fusion protein was purified using affinity chromatography with the beta(15-22)-peptide of human fibrin. RESULTS: Purified scFv(59D8)-scuPA(LMW) migrated as a 60-kDa band, which is consistent with a molecule composed of one scFv(59D8) and one scuPA(LMW) moiety. Both functions of the fusion molecule, fibrin-specific binding and plasminogen activation, were fully preserved. In human plasma clots, thrombolysis by scFv(59D8)-scuPA(LMW) is significantly faster and more potent compared with the clinically used urokinase. CONCLUSIONS: ScFv(59D8)-scuPA(LMW) constitutes a new recombinant chimeric plasminogen activator with a significantly enhanced thrombolytic potency and relative fibrin selectivity, that can be produced with modern methods at low cost, large quantities and reproducible activity in Escherichia coli.

Antibodies, Monoclonal↗
PubMed2003

[Assessment of volume responsiveness in mechanically ventilated patients].

Monitoring and management of intravascular volume status is of crucial importance in critically ill patients. Hypovolemia, induced by hemorrhage or pathologic fluid shifts in the presence of systemic inflammation, is frequently the cause for hemodynamic instability and hypotension. This deficit of central blood volume leads to a reduction in biventricular cardiac preload. With respect to the Frank-Starling mechanism, this causes an alteration in left ventricular stroke volume. If this reduction in stroke volume cannot be compensated by an increase in heart rate, this finally results in a decline of cardiac output. In this clinical situation fluid loading is the treatment of choice. However, insufficient peripheral vascular resistance and thus reduced cardiac afterload as well as impaired myocardial contractility also have to be taken in account to be causative for hypotension. Potential hazards of fluid loading specifically in the latter situation include pulmonary edema, worsening of pulmonary gas exchange and myocardial failure. Thus, prediction of fluid responsiveness, i.e. the prediction of the hemodynamic response to fluid loading is of utmost importance in critically ill patients. Several conventional parameters of systemic hemodynamic monitoring such as the cardiac filling pressures CVP and PAOP, the estimation of the left ventricular end-diastolic area (LVEDA) by echocardiography and measurement of central blood volumes as the right-ventricular end-diastolic volume (RVEDV) or the global end-diastolic volume (GEDV) by thermodilution are frequently used for preload monitoring. Further, functional preload parameters such as the left ventricular stroke volume variation (SW), describing the specific interactions of the heart and the lungs under mechanical ventilation, have been recently proposed to be useful for predicting fluid responsiveness. Thus, it is the aim of the present article to analyze these different concepts of hemodynamic monitoring regarding their usefulness and clinical applicability to predict fluid responsiveness at the bedside.

Blood Volume↗
PubMed2003

Improving selection of alphaIIbbeta3-binding phage antibodies with increased reactivity derived from immunized donors.

Although many studies of the immune response in polytransfused Glanzmann thrombasthenia (GT) patients and in autoimmune thrombocytopenic purpura (AITP) have demonstrated the frequent development of Abs directed against the alphaIIbbeta3 integrin, little is known about the induced anti-alphaIIbbeta3 autoantibodies at the molecular level. Phage display is a powerful technology for selecting and engineering mAbs expressed on the surface of filamentous bacteriophage. Combinatorial libraries of single-chain IgG were constructed from splenocytes from two patients with AITP and one patient with GT. In a previous study, activated platelets or alphaIIbbeta3-expressing CHO cells selection was performed to isolate human IgG anti-alphaIIbbeta3 binding fragments using combinatorial libraries created from the B cells of a GT and an AITP patient. However, we have experienced practical problems such as enrichment of truncated antibodies during selection. We decided to test prolonged treatments with elution agents after screening on the purified form of the alphaIIbbeta3 integrin activated with the RGD peptide. We obtained a higher percentage of clones with full-size antibody fragments as well as an enrichment of more specific alphaIIbbeta3-binding phage-Abs. Some of them, recognizing the activated form of the integrin, would be interesting to further study as potential diagnostic or therapeutic agents in acute coronary syndromes. Sequencing of selected phage-Abs revealed that they used different VH and VL genes with, for the majority of them, a high level of extensive hypermutations in the complementarity determining regions, indicating the diversity of the antigen-driven immune response that occurred in GT and AITP patients.

Animals↗
PubMed2002

Cryopreservation of reduced cytochrome C for determination of N-formyl-methionyl-leucyl-phenylalanine-stimulated superoxide anion production in human whole blood.

Various methods are available for measuring the production of reactive oxygen species by phagocytes, but they are limited in their use by the need for their immediate application, cell isolation and of cell-activation by unphysiological stimuli. In addition, after measurement of reactive oxygen metabolites using oxidizing agents, the reduced compounds formed have to be determined during or immediately after their formation. In the present study, an improved cytochrome C assay was investigated which allowed measurements of superoxide anions in whole blood samples following activation of phagocytes by physiological stimuli such as the bacterial tripeptide N-formyl-methionyl-leucyl-phenylalanine (fMLP). The fMLP-stimulated production of superoxide anion (O(2)(-)) showed a sigmoidal-shaped fMLP dose-response curve, and constant O(2)(-) production rates (nmol.1(-1)x10(6) granulocytes) could be determined reliably up to a blood granulocyte concentration of 1 x 10(4) x microl(-1). To allow the determination of reduced cytochrome C later after its formation, the effect of long-term storage at -20 degrees C on the stability of reduced cytochrome C was tested up to 16 weeks. The results obtained show that the determination of reduced cytochrome C in whole blood represents a simple and reliable method. Most importantly, O(2)(-)-reduced cytochrome C can be frozen and stored without any alterations, at least up to 2 weeks. Thus the method seems to be superior to other methods of detection, especially when the experimental conditions do not allow immediate spectrophotometry (e.g. mountain medicine, space medicine). Under such conditions the present assay would allow reliable measurement of reduced cytochrome C, even after weeks of cryopreservation.

Cell Separation↗
PubMed2002

Impact of sepsis, lung injury, and the role of lipid infusion on circulating prostacyclin and thromboxane A(2).

OBJECTIVE: To investigate whether plasma levels of prostacyclin (PGI2) and thromboxane A(2) (TxA2) are a function of the infusion rate of soybean-based fat emulsions, severity of systemic inflammation, and pulmonary organ failure. DESIGN: Prospective, randomized, crossover study. SETTING: Intensive care unit of a university hospital. PATIENTS: Eighteen critically ill patients, ten presenting with severe sepsis, eight with SIRS or sepsis complicated with ARDS. INTERVENTIONS: Patients were randomly assigned to receive rapid fat infusion over 6 h (rFI) or slow fat infusion over 24 h (sFI) along with parenteral nutrition. MEASUREMENTS AND RESULTS: The stable prostanoids 6-keto-PGF1alpha and TxB2 were measured in arterial and mixed venous blood samples, and at 6-h periods trans-pulmonary balances (TPB) were calculated. Free linoleic acid fraction was determined in arterial blood. rFI induced greater increase of linoleic acid than sFI in both groups. Enhanced prostanoid levels and correlations with linoleic acid availabilities were found, however, in ARDS patients only, revealing the highest sepsis- and lung injury scores. Averaged TPB per 24 h was positive in the sepsis group and negative in the ARDS group as rFI induced lowest TPB values for TxB2 at 6 h. CONCLUSION: The quantity of prostanoids formed and their subsequent utilization are dependent on the availability of precursor linoleic acid and are probably affected by the severity of SIRS or sepsis and the existence of pulmonary organ failure, respectively. Because TxA2 might be extracted by the injured lung, rapid infusion of soybean-based fat emulsions should be avoided in patients suffering from severe pulmonary organ failure.

Adult↗
PubMed2002

[Permissive hypotension in severe trauma].

Hemodynamic instability in the polytraumatized patient is a predominant feature and most commonly secondary to blood loss accompanying injury. In these patients restoration of intravascular volume attempting to achieve normal systemic pressure faces the risk of increasing blood loss and thereby potentially affecting mortality. Due to the lack of controlled clinical trials in this field, the growing evidence that "hypotensive resuscitation" results in improved long-term survival and improved neurologic outcome, mainly stems from experimental studies in animals. In patient care, several concepts exist for the reduction of blood loss in conjunction with systemic hypotension: these involve "deliberate hypotension" (synonym "controlled hypotension", used intraoperatively under conditions of normovolemia and stable hemodynamics), "delayed resuscitation" (where the hypotensive period is intentionally prolonged until operative intervention), and "permissive hypotension" (synonym "hypotensive resuscitation", where all kinds of therapy are commenced including fluid therapy, thereby increasing systemic pressure without, however, reaching normotension). In this review the concept of "permissive hypotension" is delineated on the basis of macro- and microcirculatory changes secondary to hypovolemia and low driving pressure, and potential indications as well as limitations for the care of the traumatized patient are discussed.

Blood Pressure↗
PubMed2002

[Electric stimulation acupuncture in peripheral neuropathic pain syndromes. Clinical pilot study on analgesic effectiveness].

AIM: The aim of this pilot study was to investigate the potential value of acupuncture in the treatment of peripheral neuropathic pain. Explorative analysis should provide data for further randomised controlled trials. METHOD: In an uncontrolled clinical trial electroacupuncture was given to 17 patients with chronic neuropathic pain of peripheral origin which was resistant to preceding pain therapy. Patients were treated twice weekly for 4 weeks. Assessment of outcome measurements comprised: Intensity of continuous pain (visual analogue scale, VAS), intensity of pain attacks (VAS), duration of pain attacks, number of pain attacks and changes in mood (VAS). All measures were evaluated by diary (1 week before treatment to 2 weeks after treatment and 1 week at follow up three months after treatment). Changes of global complaints and patients' beliefs in treatment (credibility assessment) were also assessed. RESULTS: At re-evaluation two weeks after treatment, mean continuous pain was reduced by 32.9% and intensity of pain attacks was reduced by 59%. Mean number of daily pain attacks decreased from 4.2 (SD +/- 4.6, 0.14-13.3) before treatment to 2.2 (SD +/- 3.8, 0-7.5) two weeks after treatment. Duration of pain attacks and mood showed no substantial changes. Three months after treatment, continuous pain was reduced by 15.9% and intensity of pain attacks was reduced by 44% compared to baseline. No serious adverse events were observed CONCLUSIONS: On the basis of this small pilot study, trial treatment by electroacupuncture seems to be justified in these patients given a lack of success of standard treatments. The apparent beneficial analgesic effects of electroacupuncture appear to warrant further investigation.

Acupuncture Analgesia↗
PubMed2002

Immune-modulatory actions of arginine in the critically ill.

Current trials of immune-enhancing diets suggest several beneficial clinical effects. These products are associated with a reduction in infectious risk, ventilator days, ICU and hospital stay. However, methodological weaknesses limit the inferences we can make from these studies. Furthermore, improvements in outcomes were largely seen in surgical patients and in patients who tolerated critical amounts of formula. We propose that the beneficial findings cannot easily be extrapolated to other patient populations since there is suggestion from clinical trials that the sickest patients, especially those with severest appearances of sepsis, shock and organ failure may not benefit or may even be harmed. In these conditions we hypothesize that systemic inflammation might be undesirably intensified by immune-enhancing nutrients like arginine in critically ill patients. In this paper, we review the purported effects of arginine on the immune system and organ function to understand the scientific rationale for its inclusion into enteral feeding products. We conclude that patients with the most severe appearances of the systemic inflammatory response syndrome should not receive immune-enhancing substrates which may aggravate systemic inflammation and worsen clinical outcomes.

Arginine↗