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Biomedical subjects

J R Schaefer

Publications and source records attributed to J R Schaefer.

At least 19 recordsLinked to original sources
PubMed2006

Cardiotoxicity of 5-fluorouracil.

Cardiac side effects of the cytostatic agent 5-fluorouracil (5-FU) have an incidence of 1.2-7.6%. Potentially, arrhythmias, myocardial infarction and sudden cardiac death could occur. Life-threatening cardiotoxicity is rarely observed with a frequency <1%. Cardiotoxicity of 5-FU seems to differ from well known effects of other cytostatics, e.g., anthracyclines. Myocardial ischemia was suggested as potential mechanism due to occasionally observed ECG alterations during 5-FU administration. Experimental studies revealed potential mechanisms of cardiotoxicity ranging from direct toxic effects on vascular endothelium involving endothelial NO synthase leading to coronary spasms and endothelium independent vasoconstriction via protein kinase C. In addition, rheological side effects have to be considered. Coronary artery disease is judged to increase the risk of cardiac side effects. Despite lack of prospective trials, verapamil type calcium antagonists as well as nitrates seem to be useful for treatment of 5-FU induced coronary spasms. In addition, modification of the cytostatic regimen has to be considered in patients who had been symptomatic. It could be assumed that 5-FU toxicity is reversible in the majority of cases when acute complications, e.g., arrhythmias, are resolved.

Animals↗
PubMed2005

Unsaturated fatty acids isolated from human lipoproteins activate protein phosphatase type 2Cbeta and induce apoptosis in endothelial cells.

Activity of serine/threonine protein phosphatase type 2C is known to be stimulated by certain unsaturated fatty acids and this enzyme dephosphorylates Bad, thus acting on apoptosis. This prompted us to investigate endothelial cell death. Here, we present evidence for the presence of protein phosphatase type 2Cbeta (PP2Cbeta) in human umbilical vein endothelial cells (HUVECs) and report on colocalization of PP2Cbeta and Bad in the cytosol of endothelial cells. Lipophilic compounds that stimulated PP2Cbeta activity in vitro were found to induce cell death of HUVECs. Lipoproteins did neither influence PP2Cbeta activity nor affect cell behaviour. Lipoproteins treated with the lipoprotein lipase, however, stimulated the activity of PP2Cbeta at least 10-fold concomitantly triggering cell death. Analytical methods revealed that both effects - stimulation of PP2Cbeta and apoptosis - were caused by free fatty acids liberated from VLDL, LDL and HDL with oleic acid and linoleic acid as major constituents. The results provide novel insights in endothelial apoptosis and suggest that PP2Cbeta participates in the development and progress of atherosclerosis.

Apoptosis↗
PubMed2005

Coronary artery spasm induced by 5-fluorouracil.

The frequently used chemotherapeutic drug 5-fluorouracil (5-FU) is known to cause angina pectoris and arrhythmias; myocardial infarction and sudden cardiac death could occur. Potential reasons for these phenomena range from toxic/metabolic disturbances to coronary artery spasms. This report shows angiographically proven spasmophilia of the coronary arteries and contributes to the understanding of angina pectoris occurring during treatment with 5-FU. Thus, verapamil type calcium antagonists as well as nitrates should be administered primarily in patients with coronary artery disease and in all patients who had been symptomatic during 5-FU administration in order to prevent further episodes.

Adenocarcinoma↗
PubMed2003

Novel aspects on RANK ligand and osteoprotegerin in osteoporosis and vascular disease.

The clinical coincidence of osteoporosis and vascular disease has long indicated that common mediators may adversely affect bone metabolism and vascular integrity alike. Receptor activator of NF-kappaB ligand (RANKL) is an important cytokine for bone resorption that acts through its osteoclastic receptor, receptor activator of NF-kappaB (RANK), while osteoprotegerin serves as a decoy receptor that binds RANKL and prevents activation of RANK. Skeletal and vascular cells are sources and targets of RANKL and OPG both in vitro and in vivo. Modulation of the RANKL/RANK/OPG system in animals results in a skeletal and vascular phenotype, and administration of OPG may prevent osteoporosis and vascular calcification. Recent studies on OPG serum levels and gene polymorphisms also suggest an important role of this cytokine system in skeletal and vascular diseases. In summary, there is increasing evidence that RANKL and OPG may link the skeletal with the vascular system.

Animals↗
PubMed2003

[LDL-Apheresis for the treatment of hyperchylomicronemia-induced pancreatitis].

Severe hyperchylomicronemia due to defects of lipoprotein lipase or apoC-II is a rare cause for acute pancreatitis. Food with a high content of fat, as well as alcoholic or hormonal influences, can lead to excessive hypertriglyceridemia. Especially hyperchylomicronemia due to hormonal influences during pregnancy are troublesome. Here, we are confronted with both the risk to the mother as well as the vital risk to the unborn. Conventional plasma apheresis has been used to successfully eliminate chylomicrons and, thus, the primary cause of chylomicron-induced pancreatitis. Most recently, we reported the use of selective LDL-apheresis in a 24-year-old pregnant woman (thirteenth week of pregnancy), who was admitted with the signs of acute pancreatitis to our hospital. The patient was known to have a history of severe hyperchylomicronemia and she had also been treated several years before for acute pancreatitis by LDL-apheresis. Her triglycerides were severely elevated (11500 mg/dl) and, in order to achieve a rapid decrease of chylomicrons, we decided to treat her by selective LDL-apheresis utilizing HELP-apheresis. The treatment was well tolerated and within half an hour the patient was free of any abdominal pain. However, due to the enormous triglyceride load, we needed to change the precipitate filters several times and at the end of the treatment triglyceride levels were 6600 mg/dl. Under a low-fat diet (<30 gram fat per day), the follow-up was uneventful and the patient delivered a healthy baby at the end of week 39. We conclude that LDL-apheresis is a safe and rapid procedure to eliminate chylomicrons in chylomicron-induced pancreatitis.

Adult↗
PubMed2002

[CDG (congenital disorders of glycosylation). Differential hereditary ataxia in adulthood diagnosis].

Congenital disorders of glycosylation (CDG) are a group of hereditary multisystem diseases due to different defects of enzymes or transport molecules involved in the synthesis of glycoproteins. CDG-la is the most common subtype, with cerebellar ataxia as the main neurological symptom. Currently there is little information about CDG-la manifestation in adulthood. Here we present two sisters in whom the diagnosis of CDG-la was made in the fourth decade of life and who to our knowledge are the oldest known patients with the disorder in Germany. The clinical course of the disease was typical, although less severe than previously described. The carbohydrate-deficient transferrin (CDT) level was increased but lower than in other CDG patients. Isoelectric focusing of transferrin revealed changes typical of CDG, whereas those of alpha 1-antitrypsin were only moderately pathologic. This might be due to the milder manifestation of the disease in our patients or it could be indicative of a stabilization of the disease after puberty. The CDG should be included in the differential diagnostic workup of hereditary cerebellar ataxia in adults.

Adult↗
PubMed2002

A new case of CDG-x with stereotyped dystonic hand movements and optic atrophy.

We report the clinical findings and the diagnostic work-up of a 17-month-old girl with CDG-x. Predominant clinical signs were, besides psychomotor retardation and truncal hypotonia, stereotyped dystonic hand movements and ophthalmological abnormalities such as optic atrophy, nystagmus and strabismus. Other symptoms that are often found in patients with CDG were not present, such as seizures, microcephaly, cerebellar hypoplasia, dysmorphic features, hepatointestinal disease, coagulopathy or multiorgan involvement. Isoelectric focusing (IEF) of the patient's serum showed a marked elevation of disialotransferrin, thus confirming an IEF type 1 pattern. A generalized glycosylation defect was confirmed also by IEF of a further glycoprotein (alpha1-antitrypsin), an increased carbohydrate deficient transferrin (CDT) serum concentration and an increased CDT/transferrin ratio. All known types of CDG-I, secondary glycosylation abnormalities and variants of amino acid sequence were excluded.

Dystonia↗
PubMed2002

Congenital disorder of glycosylation IId (CDG-IId) -- a new entity: clinical presentation with Dandy-Walker malformation and myopathy.

A 1.5-year-old boy with macrocephaly due to a Dandy-Walker malformation presented with progressive hydrocephalus, extensive muscular hypotonia, transient cholestatic syndrome, extensive coagulation abnormalities and elevated creatine kinase indicating myopathy. Diagnostic work-up indicated a congenital disorder of glycosylation (CDG, formerly carbohydrate deficient glycoprotein syndrome). The serum transferrin pattern obtained by automated isoelectric focusing (IEF) showed an hitherto unreported pattern with strongly elevated tri-, di-, mono- and asialotransferrin bands, increasing in this order together with markedly decreased tetrasialotransferrin. Investigation of two additional glycoproteins, alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, confirmed a generalised defect of glycosylation. All known glycosylation defects could be ruled out by enzymatic analyses in either leukocytes or fibroblasts or by the results obtained by IEF. SDS-electrophoresis demonstrated a marked difference in the molecular weight of transferrin, suggesting the lack of parts or of all oligosaccharide chains. The defect could be delineated to a deficiency of beta-1,4-galactosyltransferase (E.C.2.4.1.38) due to a homozygous insertion (1031 - 1032 insC). Details of the biochemical and molecular findings will be described elsewhere.

Adolescent↗
PubMed2001

Low hepatic lipase activity is a novel risk factor for coronary artery disease.

BACKGROUND: The crucial function of hepatic lipase (HL) in lipid metabolism has been well established, but the relationship between HL activity and coronary artery disease (CAD) is disputed. METHODS AND RESULTS: We measured HL activity in the postheparin plasma of 200 consecutive men undergoing elective coronary angiography and determined the degree of CAD with the extent score, which has been shown to be better correlated with known risk factors than other measures of CAD extent. We found a significant inverse correlation between HL activity and the extent of CAD (r=-0.19, P<0.01). This association was mainly due to patients with HDL levels >0.96 mmol/L (n=94, r=-0.30, P<0.005). HL activity was lower in 173 patients with CAD than in 40 controls with normal angiograms (286+/-106 versus 338+/-108 nmol. mL(-1). min(-1), P<0.01). To correct for potential confounding factors, we performed multivariate analyses that confirmed the independent association of HL activity with CAD extent. In addition, the presence of the T allele at position -514 in the HL promoter, which leads to a reduced HL promoter activity, was associated with lower HL activity (r=0.30, P<0.001) and higher CAD extent (42.2+/-20.8 versus 35.3+/-23.6 [extent score], P<0.05). In patients with heterozygous familial hypercholesterolemia, calcified lesions in ECG-gated spiral computed tomography were higher in patients with low HL activity (6.3+/-6.8 versus 1.5+/-3.1, P=0.01). CONCLUSIONS: Our data show that low HL activity is associated with CAD. Therefore, HL might be useful for CAD risk estimation and might be a target for pharmacological intervention.

Adult↗
PubMed2001

[Drug therapy of hyperlipidemia. Current status in Germany].

BACKGROUND: Hyperlipidemia is an important, maybe the most important, risk factor for coronary artery disease (CAD). Therefore lowering elevated cholesterol is crucial for primary and secondary prevention. Dietary treatment but also drug therapy is frequently used to lower cholesterol in our days. STATINS: Drug therapy with statins has shown to be beneficial in clinical studies. Patients at a high risk for CAD will benefit mostly of drug treatment with a statin and in one out of 13 high-risk patients statin treatment will prevent one serious cardiovascular event [NNT (number needed to treat) = 13]. This is the reason for the success story of statins in the last decade. In Germany more than 700 million defined daily doses of lipid-lowering drugs are prescribed per year, which is sufficient for continuous treatment of 1.9 million patients. However, the broad use of statins came along with some thoughtlessness towards side effects. Safety laboratory values were not determined, contraindications were not considered to be serious enough and the lack of clinical endpoint studies was neglected. In addition there was an attempt to disregulate statins as "over the counter drugs" in the US--an attempt which was stopped by the intervention of the FDA. This practice ended in a series of severe side effects and led to the withdrawal of cerivastatin, a new statin from the market. If this will influence the drug treatment of hyperlipidemia needs to be seen.

Adverse Drug Reaction Reporting Systems↗
PubMed2001

Angiography, CT and MR imaging of a high vena cava inferior interruption in a patient with Hirschsprung disease.

We report on a high vena cava inferior interruption immediately at the insertion to the right atrium in a patient with Hirschsprung disease assessed by angiography, CT, and MRI. Hirschsprung disease is frequently associated with Down, Undine, Waardenburg, Bardet-Biedl, Smith-Lemli-Opitz and Goldberg-Sphrintzen syndromes. We suggest that the association of these two malformations are most likely interrelated and should be considered as a new syndrome.

Angiography↗
PubMed2001

A new subtype of a congenital disorder of glycosylation (CDG) with mild clinical manifestations.

A boy with an unspecific symptomatology consisting of mental retardation, strabismus, hypotonia and mild ataxia was diagnosed with a congenital disorder of glycosylation (CDG). Neither cerebellar atrophy nor dysmorphic features were present. The serum transferrin band pattern obtained by isoelectric focusing(IEF) showed a strongly elevated disialotransferrin band together with only slightly elevated asialotransferrin, thus a type I pattern. This is a new CDG classified CDG-x since CDG-la, -b, -c, -d and -e were excluded. Quantitative differences to the type 1 pattern of a CDG-la patient with a moderate to severe course were confirmed by densitometric evaluation of the gels and by SDS gel electrophoresis. Liver biopsy showed lysosomal inclusions suggesting a pre-Golgi defect. This patient's case supports the approach to include isoelectric focusing of serum transferrin in the diagnostic work-up of patients with unexplained symptoms.

Asialoglycoproteins↗
PubMed2000

Strategies to optimize CAD prevention in modern cardiology. The "Marburg CAD Prevention Project".

In recent years we identified numerous cardiovascular risk factors and had been able to reduce cardiovascular events by a variety of different interventions. There is no question that we can improve the course of coronary artery disease (CAD) in patients with a high-risk profile by modifying these factors. Despite this knowledge, many patients with known CAD or myocardial infarction are not treated for secondary prevention as recommended by well established guidelines (http:¿www.chd-taskforce.com). In order to improve secondary prevention in our patients we started a project, the so called "Marburg CAD Prevention Project". By this we combine our computer data base of the CAD preventional routine laboratory with the computer program CARDDAS. Individual risk factors and the angiographic findings were analyzed. Patients as well as local physicians were informed on the need to treat the important risk factors. This approach ensures that at least all of our patients with documented CAD receive the appropriate preventional recommendations and treatment.

Adolescent↗
PubMed2000

Restenosis after percutaneous coronary interventions and infection.

Infectious agents may directly or indirectly (through the response of the host's immune system) modulate the growth of vascular cells. Local and/or systemic increase of cytokines could influence the extent of (re-)stenosis in the vascular tree. Further studies in this field may identify patients at a high risk for atherogenesis and restenosis. Their results should be helpful in treating restenosis after percutaneous coronary interventions.

Angioplasty, Balloon, Coronary↗
PubMed2000

[Impediment of cellular immune response under treatment with ticlopidine in a patient with Staphylococcus aureus endocarditis].

A 52-year-old male with coronary artery disease was admitted with acute aortic valve endocarditis and a temperature up to 39.5 degrees C caused by Staphylococcus aureus. The patient was treated with ticlopidine (Tiklyd) after percutaneous transluminal coronary angioplasties to reduce restenosis by inhibiting thrombocyte aggregation. Upon admission c-reactive protein (CRP) was 389 mg/l. Interleukin-6 (IL-6) and Interleukin-2-receptor (IL-2-rec) were distinctly increased. Monoclonal antimyocardial antibodies were found. Leukocyte count never exceeded 9.8 G/l; however, transesophageal echocardiography validated a soft vegetation of the aortic valve. Antibiotic therapy was initiated with imipenem, gentamicin and vancomycin; clarithromycin was added after five days. Temperature normalized after 24 days. The c-reactive protein decreased from 389 mg/l to 6 mg/l, and the elevated cytokine levels decreased accordingly. Agranulocytosis or pancytopenia by ticlopidine through a toxic mechanism have been described, which are normally reversible within three weeks; there has not yet been a description of a missing leukocyte response in endocarditis as in this case report. This is a special situation with lack of or impeded immunological response, which limits the use of ticlopidine, especially since a therapeutic alternative with clopidogrel is available.

Agranulocytosis↗
PubMed2000

HDL steady state levels are not affected, but HDL apoA-I turnover is enhanced by Lifibrol in patients with hypercholesterolemia and mixed hyperlipidemia.

Lifibrol (4-(4'-tert-butylphenyl)-1-(4'carboxyphenoxy)-2-butanol) is a new hypocholesterolemic drug effectively reducing total cholesterol, LDL cholesterol, and apolipoprotein (apo) B in experimental animals and in humans. In contrast to fibrates and HMG-CoA reductase inhibitors the cholesterol and triglyceride lowering effect of Lifibrol is not accompanied by increases in HDL cholesterol and apoA-I levels. We examined the impact of Lifibrol on the metabolism of HDL apoA-I in patients with hyperlipoproteinemia, using endogenous labeling with stable isotopes. Kinetic studies were performed in five male hypercholesterolemic individuals (type IIa), before and on treatment with 450 mg of Lifibrol daily for 4 weeks and in five male individuals suffering from mixed hyperlipidemia (type IIb), before and on therapy, for 12 weeks. Lifibrol reduced total cholesterol by 14% (P=0.02) and LDL cholesterol by 16% (P=0. 014) in all patients, and decreased triglycerides by 34% in type IIb patients. During Lifibrol therapy, HDL cholesterol and ApoA-I concentrations did not change. Tracer kinetics revealed that the fractional catabolic rate (FCR) of HDL apoA-I increased by 22% (P=0. 013). This increase in the apoA-I FCR was accompanied by a 23% increase in HDL apoA-I production rate (P=0.006). We conclude that Lifibrol, although not changing HDL steady state concentrations, enhances the turnover of apoA-I containing HDL particles.

Adult↗