[Reimbursement policy for ambulatory treatment of pediatric infections with ceftriaxone].
Explore the source record for details and available documents.
Ambulatory Care↗
Biomedical subjects
S Steiner
Publications and source records attributed to S Steiner.
Inflammatory cytokines interleukin-6 and oncostatin m induce plasminogen activator inhibitor-1 in human adipose tissue.
BACKGROUND: Adipose tissue is a prominent source of plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of plasminogen activation. Increased PAI-1 expression acts as a cardiovascular risk factor, and plasma levels of PAI-1 strongly correlate with body mass index (BMI). Elevated serum levels of interleukin-6 (IL-6), an inflammatory cytokine and a member of the glycoprotein 130 (gp130) ligand family, are found in obese patients and might indicate low-grade systemic inflammation. Another gp130 ligand, oncostatin M (OSM), upregulates PAI-1 in cardiac myocytes, astrocytes, and endothelial cells. We used tissue explants and primary cultures of preadipocytes and adipocytes from human subcutaneous and visceral adipose tissue to investigate whether IL-6 and OSM affect PAI-1 expression in fat. METHODS AND RESULTS: Human subcutaneous and visceral adipose tissue responded to treatment with IL-6 and OSM with a significant increase in PAI-1 production. Human preadipocytes were isolated from subcutaneous and visceral adipose tissue. Adipocyte differentiation was induced by hormone supplementation. All cell types expressed receptors for IL-6 and OSM and produced up to 12-fold increased levels of PAI-1 protein and up to 9-fold increased levels of PAI-1 mRNA on stimulation with IL-6 and OSM. AG-490, a janus kinase/signal transducer and activator of transcription inhibitor, abolished the OSM-dependent PAI-1 induction almost completely. CONCLUSIONS: We have for the first time established a link between the gp130 ligands, the proinflammatory mediators IL-6 and OSM, and the expression of PAI-1 in human adipose tissue. Thus, we speculate that IL-6 and OSM, by upregulating PAI-1 in adipose tissue, can contribute to the increased cardiovascular risk of obese patients.
Adipose Tissue↗
[Intensive care in cardiovascular medicine -- acute coronary syndrome].
Explore the source record for details and available documents.
Acute Disease↗
[Sleep apnea: significance in patients with heart failure. Pathophysiology, diagnosis and treatment].
Explore the source record for details and available documents.
Airway Obstruction↗
[Cardiovascular end organ impairment due to hypertension].
Arterial hypertension is the most frequent cause of pressure overload on the left ventricle. Longer lasting arterial hypertension leads to hypertension-specific organ manifestations summarized as "hypertensive heart disease". Hypertensive heart disease comprise the manifestation of stenosis in epicardial arteries, hypertensive microvascular disease, ischemic cardiomyopathy, left ventricular hypertrophy, endothelial dysfunction, increased sympathetic drive and degeneration of aortic valve. Diastolic dysfunction and reduced coronary flow reserve can be evaluated as early markers of hypertensive heart disease. These alterations lead to the major clinical manifestations of hypertensive heart disease that are symptoms of reduced coronary insufficiency with typical angina pectoris, but also of symptoms of heart failure (systolic and diastolic dysfunction) and arrhythmia. Different non-invasive and invasive procedures are available for screening and follow-up of patients with hypertensive heart disease. Primary therapeutic target is, apart from lowering blood pressure, to reverse cardiac manifestations of arterial hypertension using specific therapeutic algorithms.
Humans↗
[Functional dynamics of the right ventricle and pulmonary circulation in obstructive sleep apnea. Therapeutic consequences].
Obstructive sleep apnea (OSA) is common with an incidence of at least 500,000 patients in the German population. Typical symptoms are daytime sleepiness, headache in the morning, and snoring. Presumably obstructive sleep apnea via various mechanisms increases cardiovascular morbidity. Hypoxemia causes nocturnal hypertension in most of the patients. Nevertheless, about 20% of the patients develop daytime pulmonary hypertension and right heart dysfunction. Clinical and animal studies demonstrated right ventricular hypertrophy as a consequence of intermittent hypoxemia and pulmonary hypertension. Right ventricular hemodynamics differ essentially from left ventricular hemodynamics. Right ventricular function is substantially influenced by right ventricular afterload, which is mainly determined by pulmonary vascular resistance, and slightly influenced by preload. Application of continuous positive airway pressure (CPAP) via a nose mask normalizes nocturnal breathing disorders and reduces pre- and afterload, especially in patients with cardiomegaly. Therefore, CPAP generates positive effects on the myocardium.
Continuous Positive Airway Pressure↗
Disseminated microvascular pulmonary tumor cell embolism: a rare cause of fulminant pulmonary hypertension.
BACKGROUND: Disseminated pulmonary tumor embolization is a rare cause of pulmonary hypertension and is often diagnosed only after the patient has died. CASE REPORT: We report on a 41-year-old male who was admitted because of severe dyspnea and tachycardia. Contrast enhanced spiral computed tomography did neither establish pulmonary thromboembolism nor pulmonary metastasis. Right heart catheterization revealed severe pulmonary hypertension (pulmonary vascular resistance (PVR) 678 dyn x sec x cm(-5)). PVR did not respond to therapy with intravenous nitrate or inhaled iloprost in this critically ill patient. 2 days after admission, the patient died because of refractory right heart failure. Autopsy revealed microscopic pulmonary tumor embolism due to a metastasizing adenocarcinoma of the pancreas. CONCLUSION: Disseminated tumor cell embolism should be considered as a rare differential diagnosis in patients with refractory pulmonary hypertension.
Adenocarcinoma↗
[Determinants of paroxysmal atrial fibrillation in patients with arterial hypertension].
INTRODUCTION: Atrial fibrillation represents an important arrhythmia, in particular in patients with arterial hypertension. Hitherto, the connection between paroxysmal atrial fibrillation, left atrial size and left ventricular muscle mass has not been investigated sufficiently. In the present study, determinants of paroxysmal atrial fibrillation in patients with arterial hypertension were evaluated. METHODS: 104 consecutive patients were enrolled into this study. All of them suffered from arterial hypertension for more than one year. Persistent or permanent atrial fibrillation was not documented. In all of these patients, clinical, echocardiographic and rhythmologic variables were evaluated. RESULTS: In 10.3% of the patients, paroxysmal atrial fibrillation was found. These patients showed a significantly larger left atrium (43.3 +/- 6.7 vs 37.5 +/- 4.9 mm, p < 0.001), a significantly higher muscle mass of the left ventricle (152.38 +/- 43.57 vs 134.41 +/- 27.19 g/m2, p < 0.01) and significantly more frequent a mild mitral regurgitation (38.1 vs 28.6%, p < 0.01). The multivariate regression analysis revealed as independent factors for paroxysmal atrial fibrillation the size of the left atrium and the presence of mild mitral regurgitation. Independent factors for an enlarged left atrium were mitral insufficiency and left ventricular muscle mass. CONCLUSION: This study shows that paroxysmal atrial fibrillation in aterial hypertension is based on the left atrial size, and left atrial size on left ventricular muscle mass. Therefore, these results should lead to a causal therapy for treatment of paroxysmal atrial fibrillation in these patients.
Adult↗
[Catheter embolisation into the pulmonary artery. Interventional therapy of a rare form of pulmonary embolism].
Embolisation of a foreign body is a rare cause of pulmonary embolism. We report on a 67 year old female suffering from colorectal cancer. To perform adjuvant chemotherapy a port system was inserted into the right subclavian vein. Routine chest radiography revealed a rupture of the venous port-system, which was embolised into the right pulmonary artery without clinical symptoms. The foreign body was removed without complications using a nitinol goose neck snare via a transfemoral approach and retrieved percutaneously. The reported procedure is safe, decreases operation and hospitalisation time and should therefore be performed in preference to surgical management whenever possible.
Aged↗
Technosphere/Insulin--proof of concept study with a new insulin formulation for pulmonary delivery.
Summary.Technosphere/Insulin (TI) is a formulation of regular human insulin and Technosphere, a new drug delivery system for pulmonary administration. The formulation is designed for efficient transport of insulin across the intact respiratory epithelium into the systemic circulation. We have investigated the pharmacodynamic and pharmacokinetic properties of Technosphere/Insulin in five healthy, non-smoking volunteers. In an open, randomized, three-way crossover study, subjects received 5 IU regular human insulin (HI) intravenously, 10 IU HI subcutaneously; and 100 IU TI via inhalation using a small commercially available asthma inhaler. The time action profiles of all three insulin formulations were assessed by the euglycemic glucose clamp technique on three different study days. Glucose infusion rates were monitored from 2 h before until 6 h after insulin administration. Other study measures were serum insulin, serum C-peptide concentrations, and safety parameters. The inhalation of TI was well tolerated. The time to peak action was significantly shorter with both i.v. injection and inhalation, as compared to s.c. (14 +/- 6 min and 39 +/- 36 min vs. 163 +/- 25 min; p < 0.0002 and p < 0.007 (mean +/- SD)). The metabolic effect during the first 3 h after insulin administration was higher with inhaled TI than with HI s.c. (AUC0-180 for glucose infusion rate: 1.94 +/- 0.77 mg/kg * min vs. 1.15 +/- 0.50 mg/kg * min; p < 0.04). Relative and absolute bioavailability for the first 3 h were 26 +/- 12% and 15 +/- 5% respectively (6 h: 16 +/- 8 and 16 +/- 6%). We conclude that inhalation of TI leads to a rapid onset of metabolic action resembling the effect observed with i.v. administration of regular HI. Despite the use of a common asthma inhaler, bioavailability over the three hour prandial period was substantially greater than with other reported pulmonary systems. Therefore, inhalation of Technosphere/Insulin may become a suitable and attractive alternative for prandial insulin delivery, especially for patients with type 2 diabetes mellitus.
Adult↗
Cholesterol biosynthesis regulation and protein changes in rat liver following treatment with fluvastatin.
The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a key regulator in cholesterol biosynthesis and HMG CoA reductase inhibitors (statins) have become a widely prescribed family of lipid lowering agents. Cholesterol synthesis occurs predominantly in liver which is the target organ of statins. We studied the effects of fluvastatin (Lescol), a member of the statin family, on hepatic protein regulation. Male F344 rats treated with 0.8 mg/kg per day fluvastatin or 24 mg/kg per day fluvastatin for 7 days showed treatment-related changes in 58 liver proteins (P<0.005). Major effects were evident in the cholesterol biosynthesis pathway including the induction of enzymes upstream and downstream of the target enzyme HMG CoA reductase. Treatment also triggered alterations in key enzymes of carbohydrate metabolism and was associated with changes in a heterogeneous set of cellular stress proteins involved in cytoskeletal structure, calcium homeostasis and protease activity. The latter set of protein alterations indicates that hepatotoxicity is associated with high-dose treatment. Based on the results it is suggested that HMG-CoA synthase and isopentenyl-diphosphate delta-isomerase may be explored as alternative drug targets and that the induction levels of these enzymes may serve as a measure of potency of individual statin drugs. It is proposed that efficacy and cellular stress markers discovered in this study may be used in a high throughput screen (HTS) assay format to compare efficiently and accurately the therapeutic windows of different members of the statin family.
Animals↗
Precious things come in little packages.
The 110-amino acid multidrug transporter from E. coli, EmrE, is a member of the family of MiniTexan or Smr drug transporters. EmrE can transport acriflavine, ethidium bromide, tetraphenylphosphonium (TPP+), benzalkonium and several other drugs with relatively high affinities. EmrE is an H+/drug antiporter, utilizing the proton electrochemical gradient generated across the bacterial cytoplasmic membrane by exchanging two protons with one substrate molecule. The EmrE multidrug transporter is unique in its small size and hydrophobic nature. Hydropathic analysis of the EmrE sequence predicts four alpha-helical transmembrane segments. This model is experimentally supported by FTIR studies that confirm the high alpha-helicity of the protein and by high-resolution heteronuclear NMR analysis of the protein structure. The TMS of EmrE are tightly packed in the membrane without any continuous aqueous domain, as was shown by Cysteine scanning experiments. These results suggest the existence of a hydrophobic pathway through which the substrates are translocated. EmrE is functional as a homo-oligomer as suggested by several lines of evidence, including co-reconstitution experiments of wild-type protein with inactive mutants in which negative dominance has been observed. EmrE has only one membrane embedded charged residue, Glu-14, that is conserved in more than fifty homologous proteins and it is a simple model system to study the role of carboxylic residues in ion-coupled transporters. We have used mutagenesis and chemical modification to show that Glu-14 is part of the substrate-binding site. Its role in proton binding and translocation was shown by a study of the effect of pH on ligand binding, uptake, efflux and exchange reactions. We conclude that Glu-14 is an essential part of a binding site, common to substrates and protons. The occupancy of this site is mutually exclusive and provides the basis of the simplest coupling of two fluxes. Because of some of its properties and its size, EmrE provides a unique system to understand mechanisms of substrate recognition and translocation.
Amino Acid Sequence↗
Expression profiling in toxicology--potentials and limitations.
Recent progress in genomics and proteomics technologies has created a unique opportunity to significantly impact the pharmaceutical drug development processes. The perception that cells and whole organisms express specific inducible responses to stimuli such as drug treatment implies that unique expression patterns, molecular fingerprints, indicative of a drug's efficacy and potential toxicity are accessible. The integration into state-of-the-art toxicology of assays allowing one to profile treatment-related changes in gene expression patterns promises new insights into mechanisms of drug action and toxicity. The benefits will be improved lead selection, and optimized monitoring of drug efficacy and safety in pre-clinical and clinical studies based on biologically relevant tissue and surrogate markers.
Animals↗
Evidence for the impairment of the vitamin D activation pathway by cyclosporine A.
Cyclosporine A (CsA) is a potent immunosuppressant with the drawback of renal side effects. We reported that CsA markedly decreases calcium-binding protein calbindin-D28k mRNA levels in rat kidneys, and showed that this decrease is associated with its adverse renal effects. The transcription of the calbindin-D28k gene is activated via the vitamin D pathway. In this work, the potential CsA-mediated impairment of the vitamin D pathway was investigated. Wistar rats were treated for 12 days with 50 mg/kg/day CsA or for 20 days with 50 mg/kg/day of the non-immunosuppressant and non-nephrotoxic SDZ PSC 833, which had been previously shown not to affect calbindin-D28k mRNA levels. The expression of the three vitamin D-regulated genes calbindin-D28k, 1,25-dihydroxyvitamin D3-24-hydroxylase (24-OHase), and vitamin D receptor (VDR) were quantified in rat kidney homogenates by real-time reverse transcription-polymerase chain reaction. Plasma parathyroid hormone (PTH) as well as plasma and kidney 1,25 dihydroxyvitamin D3 (calcitriol) levels were monitored in all animals. CsA induced a 85% decrease in calbindin-D28k mRNA levels as well as a 40% and 69% decrease in VDR and 24-OHase mRNA levels, respectively. Plasma and kidney 1,25 dihydroxyvitamin D3 as well as plasma PTH levels were increased by CsA, but not by SDZ PSC 833. The treatment with SDZ PSC 833 did not affect calbindin-D28k or VDR expression, but did cause a 73% decrease in 24-OHase mRNA levels. Taken together, these results indicate an association between CsA-mediated down-regulation of rat renal calbindin-D28k mRNA and the decrease in other 1,25 dihydroxyvitamin D3-regulated genes, suggesting an impairment of the vitamin D pathway by CsA which may be related to its adverse renal side effects and its immunosuppressive activity.
Animals↗
Proteomics: applications and opportunities in preclinical drug development.
Advances in DNA sequencing and the near-term availability of whole genome sequences for several pharmaceutically relevant organisms promise to dramatically alter the breadth and scale of high-throughput proteomic studies. The substantial amount of literature is available in the public domain, demonstrate the potential of proteomics in the preclinical phases of pharmaceutical development. Over the next few years, it is anticipated that functional genomics and proteomics will have major impacts on the clinical phases of drug development. Expected benefits are earlier proof-of-concept studies in man and increased efficiency of clinical trials through the availability of biologically relevant markers for drug efficacy and safety.
Drug Design↗
Two-dimensional electrophoresis of liver proteins: characterization of a drug-induced hepatomegaly in rats.
Two-dimensional electrophoresis (2-DE) of liver proteins was applied to further characterize an unusual drug-induced increase in hepatocellular rough endoplasmic reticulum (RER) in Sprague-Dawley rats given a substituted pyrimidine derivative. Absolute liver weights of drug-treated rats (9.9 +/- 0.4 g) increased above vehicle-treated controls (7.2 +/- 0.2 g) by 37%. Light microscopy revealed diffuse granular basophilia of the hepatocellular cytoplasm, uncharacteristic of hepatocytes and suggested cells rich in ribosomes, which was confirmed by electron microscopy. Immunostaining for cell proliferation, viz., 5-bromo-2'-deoxyuridine (BrdU) and proliferating cell nuclear antigen (PCNA), indicated marked hepatocellular proliferative activity. 2-DE of solubilized liver using an ISO-DALT gel system indicated significant (p<0.001) quantitative changes in at least 17 liver proteins (12 increased, 5 decreased) compared to controls. The protein with the largest increase was homologous to acute-phase reactant, contrapsin-like protein inhibitor-6. Other markedly upregulated proteins were methionine adenosyltransferase, a catalyst in methionine/ATP metabolism and mitochondrial HMG-CoA synthase, involved in cholesterol synthesis. The complementary strategies of 2-DE coupled either with database spot mapping or protein isolation and amino acid sequencing successfully identified a subset of proteins from xenobiotic-damaged rodent livers, the expression of which differed from controls. However, the current bioinformatics platform for rodent hepatic proteins and limited knowledge of specific protein functionality restricted application of this proteomics profile to further define a mechanistic basis for this unusual hepatotoxicity.
Animals↗
Proteomics to display lovastatin-induced protein and pathway regulation in rat liver.
Lovastatin is a lipid lowering agent that acts by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a key regulatory enzyme in cholesterol biosynthesis. In this study the pattern of gene network regulation induced in hepatic proteins as a response to lovastatin treatment was analyzed by proteomics. In livers of male F344 rats treated with 1.6 mg/kg/day lovastatin or 150 mg/kg/day lovastatin for seven days, 36 proteins were found to be significantly altered (p<0.001) in relation to treatment. The changed proteins were classified according to their cellular function and participation in biochemical pathways. The following observations were made: (i) inhibition of HMG-CoA reductase provoked a regulatory response in the cholesterol synthesis pathway including the induction of cytosolic HMG-CoA synthase and of isopentenyl-diphosphate delta-isomerase, (ii) manipulation of the lipid metabolism triggered alterations in key enzymes of the carbohydrate metabolism, and (iii) lovastatin treatment was associated with signs of toxicity as reflected by changes in a heterogeneous set of cellular stress proteins involved in functions such as cytoskeletal structure, calcium homeostasis, protease inhibition, cell signaling or apoptosis. These results present new insights into liver gene network regulations induced by lovastatin and illustrate a yet unexplored application of proteomics to discover new targets by analysis of existing drugs and the pathways that they regulate.
Amino Acids↗
Sudden onset of EDTA-dependent pseudothrombocytopenia after therapy with the glycoprotein IIb/IIIa antagonist c7E3 Fab.
The development of thrombocytopenia following exposure to the platelet glycoprotein (GP) IIb/ IIIa receptor antagonist abciximab (c7E3 Fab, ReoPro) is associated with adverse clinical outcome and excessive bleeding. Pseudothrombocytopenia is an important differential diagnosis in sudden onset of thrombocytopenia in a patient treated with c7E3 Fab. We report on a case of documented sudden onset of EDTA-dependent pseudothrombocytopenia in a 63-year-old woman who was admitted for emergency coronary intervention. Four hours after bolus administration of c7E3 Fab, the platelet concentration in EDTA-anticoagulated blood decreased from 385 x 10(9)/l to 119 x 10(9)/l, and it showed a further decrease to 57 x 10(9)/l at the end of a 12-h infusion. Despite no warnings or abnormalities of the automated cell counter, platelet aggregates were observed by microscopic evaluation of the blood smear. Repeated platelet counts in citrate-anticoagulated samples revealed platelet concentrations within the reference range. EDTA-dependent pseudothrombocytopenia due to therapy with c7E3 Fab is an important differential diagnosis that needs to be excluded rapidly from other causes of thrombocytopenia to avoid unnecessary further examinations, discontinuation of therapy, or even initiation of inappropriate therapy.
Abciximab↗