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Biomedical subjects

J R Schaefer

Publications and source records attributed to J R Schaefer.

At least 37 records · Page 2Linked to original sources
PubMed2000

An X-linked gene involved in androgenetic alopecia: a lesson to be learned from adrenoleukodystrophy.

BACKGROUND: Adrenoleukodystrophy (ALD), including its adult variant adrenomyeloneuropathy (AMN), is an X-linked recessive trait characterized by progressive demyelinization of the nervous system. The gene defect involves a peroxisomal transporter protein, resulting in accumulation of very-long-chain fatty acids in the brain and other organs such as the adrenal glands. Affected men show various endocrine disorders. Moreover, disturbances of hair growth are frequently mentioned in reports on ALD/AMN. OBJECTIVE: This study was performed to delineate further the hair status and type of hair loss in men with AMN. METHODS: We examined and documented the status of hair growth in 16 men suffering from AMN. A meticulous history with particular regard to hair changes was taken from all patients and their family members. RESULTS: The age of the patients varied between 27 and 62 years, their mean age was 39.8 years. Twelve men showed male-pattern androgenetic alopecia (AGA), Hamilton grades IV-VIII, 3 men had a female-pattern AGA (Ludwig grade I or II). Ten of the patients with male-pattern AGA had reached Hamilton stage VII or VIII. The remaining scalp hair was unusually scarce and thin in 11 cases, regardless of the grade of AGA. Moreover, in 10 of 16 patients the eyelids showed pronounced madarosis. The remaining body hair was found to be normal. If present, endocrine manifestations had started prior to the onset of alopecia, and in 11 of 12 patients hair loss was apparent before neurological symptoms were noted. CONCLUSION: ALD/AMN gives rise to two different types of hair loss. Firstly, affected men show diffuse hair loss involving the entire scalp and the eyelashes. Secondly, they tend to develop AGA more frequently and earlier and in a severer form. Paradoxically, pronounced AGA is present although the patients may simultaneously show some degree of hypogonadism. Hence, the X-linked ALD mutation can be taken as a well-defined gene within the polygenic spectrum of genes responsible for AGA. This may be of theoretical importance for the elucidation of the pathogenetic pathways of AGA.

Adrenoleukodystrophy↗
PubMed2000

Increased production of HDL ApoA-I in homozygous familial defective ApoB-100.

Familial defective apolipoprotein (apo) B-100 (FDB) is a frequent cause of hypercholesterolemia. Hypercholesterolemia in homozygous FDB is less severe than in homozygotes for familial hypercholesterolemia. Recently, we showed decreased low density lipoprotein (LDL) apoB-100 fractional catabolism and decreased production of LDL due to an enhanced removal of apoE-containing precursors in a patient with homozygous FDB. The effects of defective apoB-100 on high density lipoprotein (HDL) metabolism are unknown. We studied HDL apoA-I metabolism in this FDB patient and in 6 control subjects by using (2)H(3)-L-leucine as a tracer. ApoA-I levels were normal in all study subjects. However, the fractional catabolic rate and the production rate of apoA-I were increased, by 79% and 70%, respectively, in FDB; the fractional catabolic rate of apoA-I in FDB was 0.34 day(-1) compared with 0.19+/-0.03 day(-1) in normal controls. The production rate of apoA-I in FDB was 18.4 mg. kg(-1). d(-1) compared with 10.8+/-2.3 mg. kg(-1). d(-1) in controls. Thus, we have shown for the first time that defective apoB-100 may influence HDL kinetics. The increase in total HDL turnover might enhance reverse cholesterol transport and could contribute to the seemingly benign clinical course of FDB compared with that of familial hypercholesterolemia.

Adult↗
PubMed2000

Hyperinsulinemia, lipoprotein (a), and Chlamydia pneumoniae antibodies--are they risk factors or serologic predictors for progression of coronary artery disease?

The authors studied 134 patients with unstable angina pectoris symptoms and 32 subjects without coronary artery disease (CAD) for the presence of classical risk factors such as hypercholesterolemia, smoking, and family history of CAD. In addition they analyzed plasma insulin levels, lipoprotein (a) (Lp [a]) levels, and antibody titers against Chlamydia pneumoniae. All patients had a heart catheterization. Patients with diabetes mellitus were excluded from the study. Fasting insulin, low-density lipoprotein (LDL) cholesterol and Chlamydia pneumoniae immunoglobulin G (IgG) and IgA antibody titers did not show any difference in CAD from healthy control subjects, whereas Lp(a) was increased and high-density lipoprotein (HDL) decreased in CAD patients. These data indicate that lipoprotein (a), low HDL cholesterol, and smoking, but neither hyperinsulinemia nor elevated Chlamydia pneumoniae titers, are risk factors or predictors for CAD.

Angina, Unstable↗
PubMed2000

Investigation by isoelectric focusing of the initial carbohydrate-deficient transferrin (CDT) and non-CDT transferrin isoform fractionation step involved in determination of CDT by the ChronAlcoI.D. assay.

BACKGROUND: The introduction of a new set of reagents for the determination of carbohydrate-deficient transferrin (CDT) as a marker of chronic alcohol abuse requires an independent evaluation of the analytic specificity of the test. This information is needed for correct interpretation and classification of test results. METHODS: Isoelectric focusing on the PhastSystem(TM) followed by immunofixation, silver staining, and densitometry was used to validate the initial transferrin isoform fractionation step on anion-exchange microcolumns involved in the ChronAlcoI.D. assay. RESULTS: The in vitro transferrin iron load was complete and stable. The CDT and non-CDT transferrin fractionation on anion-exchange microcolumns was reliable and reproducible (CV < or = 10%). Except for quantitatively unimportant traces of trisialo-Fe(2)-transferrin (<5% of total CDT), only asialo-, mono-, and disialo-Fe(2)-transferrin were detected in the microcolumn eluates (n = 170). There was a loss of proportionally similar amounts of asialo-Fe(2)-transferrin (during column rinsing) and disialo-Fe(2)-transferrin (on the anion exchanger). Thus, the peak height ratios for disialo- and asialo-Fe(2)-transferrin did not change from >1 (serum) to <1 (eluates) as described for the CDTect assays. The transferrin patterns in the ChronAlcoI.D. eluates were representative of those in serum. Transferrin D variants with isoelectric points close to that of trisialo-Fe(2)-transferrin C1 did not cause overdetermination of CDT by the ChronAlcoI.D. test. CONCLUSIONS: The initial CDT and non-CDT fractionation step involved in determination of CDT by the ChronAlcoI.D. assay is efficient for eliminating non-CDT transferrins from serum before quantification of CDT in the final turbidimetric immunoassay. We recommend IEF for validation of other (commercial) CDT analysis methods and of odd CDT results.

Biomarkers↗
PubMed1999

[Prevention of coronary heart disease--"evidence-based medicine" of antilipemic therapy].

A considerable number of large scale clinical trials provide clear evidence that cholesterol lowering is one of the most important risk-reduction strategies for secondary and primary prevention of coronary artery disease. Unlike the older studies with fibrates, the most recent trials of cholesterol-lowering therapies with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have clearly shown that their use can reduce coronary artery disease and total mortality as well as the need for expensive hospitalization and revascularization procedures. Studies such as the Scandinavian Simvastatin Survival Study (4S), the West of Scotland Coronary Prevention Study (WOS), the Cholesterol and Recurrent Events (CARE) trial and most recently the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) as well as numerous other investigations, have established that decreasing elevated levels of low-density lipoprotein (LDL) cholesterol will result in a reduction in risk of coronary artery disease. In addition, HMG-CoA reductase inhibition reduces the risk for cerebral ischemia. Recent data indicate that less than half of patients with coronary artery disease receive cholesterol-lowering therapy, and few meet the LDL-cholesterol goal. Therefore clinicians treating coronary artery disease need to emphasize secondary prevention and recognize the key role of cholesterol-lowering therapy. The challenge for clinicians is to apply the important lessons learned from these clinical trials to an "evidence-based" patient care.

Anticholesteremic Agents↗
PubMed1999

[Laboratory diagnosis in preventive cardiology].

In recent years a large number of coronary artery disease risk factors were discovered. The knowledge of these factors improves the estimate of the coronary artery disease (CAD) risk--however it still remains to be only an "estimate". A perfect prediction of an upcoming CAD event is not possible, despite all high score laboratory technology. Therefore the use of specialized laboratory procedures should be applied carefully. Knowing the blood levels of cholesterol, triglycerides, HDL- and LDL-cholesterol and Lp(a) can be sufficient for many therapeutical decisions. Severe dyslipidemia, familial CAD and CAD without any obvious reasons demand a more specialized work-up, however, risk stratification factors such as family history, clinical history (CAD, hypertension, diabetes mellitus, smoker) and genetics are crucial, apart from the above mentioned laboratory values. Purely on the basis of the lipidologic baseline concentrations we can't give well based recommendations for the treatment of individual patients. Currently there are expert systems available which allow a risk estimate once important laboratory values (LDL cholesterol, HDL cholesterol, Triglycerides) as well as clinical data (blood pressure, family history, clinical history) are available. This system can be accessed by internet under "http:/(/)www.chd-taskforce.com".

Coronary Artery Disease↗
PubMed1999

Metabolic basis of high density lipoproteins and apolipoprotein A-I increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease.

HMG-CoA reductase inhibitors, such as pravastatin, are widely used as lipid lowering drugs in hypercholesterolemia. Pravastatin does not only reduce the atherogenic low density lipoprotein (LDL)-cholesterol, but is also increasing high density lipoprotein (HDL)-cholesterol. However, the mechanism leading to an increase of HDL are unclear. Therefore, the effects of pravastatin on the in vivo kinetics of apolipoprotein (apo) A-I were studied in six normolipidemic subjects and in a patient with coronary artery disease (CAD) utilizing stable isotope tracer techniques. Two turnover studies were performed. The first turnover study was carried out before any drug treatment, the second study after 6 weeks of 40 mg pravastatin/day. Three times deuterium labeled L-leucine (3D-leucine) was given as a primed bolus constant infusion (bolus: 1340 microg/kg; infusion: 22 microg/kg per h), and tracer uptake into HDL apoA-I was determined by gas chromatography (GC)-mass-spectrometry (MS). In the healthy subjects HDL-cholesterol increased by 13% and apoA-I increased by 12% under pravastatin treatment. The HDL in the CAD patient decreased by 3% and apoA-I increased by 2%. Prior to drug treatment the mean apoA-I fractional synthetic rate (FSR) was 0.194 per day (S.D. +/- 0.02) and apoA-I production rate (PR) was 10.8 mg/kg per day (S.D. +/- 2.1). The CAD patient had a FSR of 0.219 per day and a PR of 10.6 mg/kg per day. After treatment with pravastatin the mean apoA-I FSR was 0.204 per day (S.D. +/- 0.02) and apoA-I PR was 12.5 mg/kg per day (S.D. +/- 1.5) in the healthy subjects. Despite only minor changes of HDL and apoA-I in the CAD patient, there were significant changes of FSR (0.267 per day) and PR (13.1 mg/kg per day) with pravastatin treatment. The in vivo kinetic data demonstrate an increased FSR of apoA-I. The increase in apoA-I is due to an increased PR of apoA-I. This study demonstrates increased production of HDL apoA-I as the metabolic cause of the increase in HDL and apoA-I levels under inhibition of HMG-CoA reductase in man.

Adult↗
PubMed1999

Semi-automated rapid isoelectric focusing of apolipoproteins C from human plasma using Phastsystem and immunofixation.

Apolipoproteins (apo) C-I, C-II, and C-III play crucial roles in intravascular lipid metabolism. Whereas apo C-II is an obligate cofactor for lipoprotein lipase, apo C-III was shown to inhibit its action. Apo C-I can be a potent cofactor of human lecithin:cholesterol acyltransferase. Structural mutants and deficiencies of apo C-II lead to hypertriglyceridemia. A similar phenotype is associated with apo C-III mutants and is inducible by overexpression of human apo C-III in transgenic animals. No structural variant has so far been reported for apo C-I. The present paper describes a rapid semi-automated procedure for isoelectric focusing analysis of these C-apolipoproteins from whole plasma or serum and their visualization by immunofixation and silver staining. The procedure allows detection of charged variants of C-apolipoproteins. As applied to 295 patients with coronary heart disease and 85 controls, it also serves to detect deficiency syndromes of these apolipoproteins. The procedure provides reliable, easy and quick analysis of C-apolipoproteins applicable as a routine or screening procedure not restricted to specialized laboratories.

Acrylic Resins↗
PubMed1998

[Arteriosclerosis and coronary heart disease--strengths and weaknesses in the classical risk factor concept].

Several cardiovascular risk factors were identified (high LDL-cholesterol, low HDL-cholesterol, homocystein, Lp(a), and many others). Hypercholesterolemia has been shown to be one of the most important cardiovascular risk factors in man. Interventional studies for primary and secondary prevention demonstrate a beneficial effect of cholesterol lowering therapy. However, numerous CAD-patients suffer a second coronary event despite the appropriate lipid-lowering treatment. Furthermore moderate hypercholesterolemia has only poor predictive power indicating an upcoming myocardial infarction. Therefore we need additional research in CAD prevention and in identifying so far unknown or unconsidered CAD risk factors.

Coronary Artery Disease↗
PubMed1998

[Cytomegalovirus and herpes simplex virus in pathogenesis and progression of native arteriosclerosis and recurrent stenosis after intervention].

An increasing number of clinical and experimental studies point to a contribution of various infectious organisms like chlamydia pneumoniae or herpesviruses to atherosclerosis in man. Cytomegalovirus induces atherosclerotic lesions in animals. In vitro studies reveal functional changes of endothelial cells after infection with cytomegalovirus. Infection with this virus renders endothelial cells immunogenic for cellular and humoral immune reactions. In man a significant association of infections with herpesviruses and atherosclerosis could be established in several studies. Cytomegalovirus infection has been incriminated as an independent risk factor in restenosis after coronary angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1997

Homozygous familial defective apolipoprotein B-100. Enhanced removal of apolipoprotein E-containing VLDLs and decreased production of LDLs.

Familial defective apolipoprotein B-100 (FDB) is a frequently inherited disorder of lipoprotein metabolism. The glutamine-for-arginine substitution at position 3500 of apolipoprotein (apo) B-100 leads to defective binding of apo B-100 to the low density lipoprotein (LDL) receptor and accumulation of LDL in the plasma. We recently identified a patient homozygous for this mutation. His LDL cholesterol and apo B concentrations were approximately twice normal, whereas his apo E plasma level was low. Using a stable-isotope labeling technique ([2H3]leucine-primed constant infusion), we studied lipoprotein turnover in vivo in the fasting state in this patient and three clinically healthy, normolipidemic individuals not carrying the FDB mutation. The residence time of LDL apo B-100 was prolonged 3.6-fold in the FDB homozygote (8.3 vs 2.3 days). The production rate of LDL apo B-100 was decreased (7.4 vs 15 mg per kg per day). In FDB the residence time of very low density lipoprotein (VLDL) apo B-100 was longer (2.6 vs 1.3 hours), whereas the residence time of VLDL apo E was shorter (2.6 vs 4.5 hours) than normal. These data show that the in vivo metabolism of apo B-100-containing lipoproteins in FDB is different from that in familial hypercholesterolemia, in which LDL receptors are defective. In both conditions the residence times of LDL apo B-100 appear to be increased to approximately the same degree. This contrasts with the LDL apo B-100 synthetic rate, which is increased in familial hypercholesterolemia and decreased in FDB. The decreased production of LDL apo B-100 in FDB may originate from enhanced removal of apo E-containing LDL precursors by LDL receptors, which may be upregulated in response to the decreased flux of LDL-derived cholesterol into hepatocytes.

Apolipoprotein B-100↗
PubMed1996

Determination of isotopic ratios of L-leucine and L-phenylalanine and their stable isotope labeled analogues in biological samples by gas chromatography/triple-stage quadrupole mass spectrometry.

A gas chromatographic/triple-stage quadrupole mass spectrometric (GC/MS/MS) method for measuring very low levels of enrichment of [5,5,5-2H3]-L-leucine and [ring-13C6]-L-phenylalanine in plasma and lipoprotein hydrolysates is described. The amino acids were derivatized to their N-heptafluorobutyryl isobutyl ester derivatives and the isotope ratio was determined by GC/MS/MS in the negative-ion chemical ionization mode. Parent ions were the [M-HF]- ions and fragment ions used for quantification were [P-2HF-C3H7]- (leucine) and [P-HF-OC4H9]- (phenylalanine), respectively. The limit of quantification was about 10 pg of the labeled compound co-eluting with 20 ng of the endogenous compound. The calibration curves were linear in the investigated range from 0.1% to 100% of the labeled compound. In biological samples, the higher selectivity of GC/MS/MS compared with GC/MS was demonstrated.

Apolipoprotein A-I↗
PubMed1995

[Oral contraceptive-induced pancreatitis in the hyperchylomicronemia syndrome].

A now 24-year-old woman was found at the age of 2 years to have an hyperchylomicronaemia syndrome due to lipoprotein lipase deficiency: the triglyceride level was then 6000 mg/dl. But in subsequent years it had been reduced to between 550 and 2600 mg/dl by dieting. There were no xanthomas or abdominal symptoms during those years. When aged 20 years she was put on oral contraceptives (one-phase preparation: 0.03 mg ethinylestradiol and 0.075 gestodene). Six months later she had the first attack of severe necrotizing pancreatitis; three more attacks followed in the subsequent 6 months. All four attacks occurred during the drug-free period of the menstrual cycle. The relationship with contraceptive intake was not established until the fourth attack. The last acute pancreatitis (lipase 3283 U/l amylase 595 U/l, triglyceride 2400 mg/dl, WBC count 13,899/microliters; ultrasonography revealed fluid swelling and necrotic areas, especially around the splenic hilus) regressed within 5 days and has not recurred for 3 years after the patient stopped taking oral contraceptives. On a diet the triglyceride level has been around 880 mg/dl.

Acute Disease↗
PubMed1995

Apolipoprotein AI, AII, and AIV isoforms in plasma determined by automated isoelectric focusing with PhastSystem and immunofixation.

Distinct genetic variants of apolipoprotein (apo) AI have been shown to influence concentrations of high-density lipoprotein (HDL) cholesterol. The genetic polymorphism of apo AIV may modulate HDL-cholesterol, plasma triglycerides, and lipoprotein(a) concentrations. There is evidence for an antagonizing role of apo AII in reverse cholesterol transport. Since genetic polymorphisms and variants of these apolipoproteins are detectable by isoelectric focusing (IEF), we developed a rapid and easy automated method for IEF analysis of apos AI, AII, and AIV on self-made or commercially available gels, using the PhastSystem. Diluted plasma or serum samples (1 microL) are applied automatically onto the gel and IEF is carried out for 35-45 min. Afterwards, the apo A bands are precipitated by specific polyclonal antibodies and visualized by automated silver staining. This rapid procedure is suitable as a routine or screening method for IEF analysis of these major HDL apolipoproteins.

Apolipoprotein A-I↗
PubMed1993

Increased production of apolipoprotein A-I associated with elevated plasma levels of high-density lipoproteins, apolipoprotein A-I, and lipoprotein A-I in a patient with familial hyperalphalipoproteinemia.

Familial hyperalphalipoproteinemia (FHA) is a heritable trait associated with elevated plasma concentrations of high-density lipoprotein (HDL) cholesterol and possibly with longevity and protection against coronary heart disease (CHD). The metabolic basis and molecular etiology of FHA have not been established in most kindreds. The proband of a kindred with FHA and possible longevity was found to have elevated plasma levels of HDL cholesterol, apolipoprotein (apo) A-I, and lipoproteins containing apo A-I without apo A-II (Lp A-I), but normal levels of apo A-II and lipoproteins containing apo A-I with apo A-II (Lp A-I:A-II). The in vivo kinetics of apo A-I and apo A-II were studied in the FHA proband and in control subjects using both exogenous radiotracer (125I-apo A-I and 131I-apo A-II) and endogenous stable isotope (primed constant infusion of 13C6-phenylalanine) labeling techniques. The production rate (PR) of apo A-I was markedly increased in the FHA subject (28.9 mg/kg.d) compared with the control subjects (12.0 +/- 2.1 mg/kg.d), whereas the apo A-II PR was not substantially increased. The primary sequence of the proband's apo A-I gene, including 1.2 kb of the 5'-flanking sequence, was normal. We conclude that a selective upregulation of apo A-I production is one metabolic cause of FHA, and results in high plasma concentrations of HDL cholesterol, apo A-I, and Lp A-I and possibly in protection from atherosclerotic CHD.

Apolipoprotein A-I↗
PubMed1993

Delayed catabolism of high density lipoprotein apolipoproteins A-I and A-II in human cholesteryl ester transfer protein deficiency.

Deficiency of the cholesteryl ester transfer protein (CETP) in humans is characterized by markedly elevated plasma concentrations of HDL cholesterol and apoA-I. To assess the metabolism of HDL apolipoproteins in CETP deficiency, in vivo apolipoprotein kinetic studies were performed using endogenous and exogenous labeling techniques in two unrelated homozygotes with CETP deficiency, one heterozygote, and four control subjects. All study subjects were administered 13C6-labeled phenylalanine by primed constant infusion for up to 16 h. The fractional synthetic rates (FSRs) of apoA-I in two homozygotes with CETP deficiency (0.135, 0.134/d) were found to be significantly lower than those in controls (0.196 +/- 0.041/d, P < 0.01). Delayed apoA-I catabolism was confirmed by an exogenous radiotracer study in one CETP-deficient homozygote, in whom the fractional catabolic rate of 125I-apoA-I was 0.139/d (normal 0.216 +/- 0.018/d). The FSRs of apoA-II were also significantly lower in the homozygous CETP-deficient subjects (0.104, 0.112/d) than in the controls (0.170 +/- 0.023/d, P < 0.01). The production rates of apoA-I and apoA-II were normal in both homozygous CETP-deficient subjects. The turnover of apoA-I and apoA-II was substantially slower in both HDL2 and HDL3 in the CETP-deficient homozygotes than in controls. The kinetics of apoA-I and apoA-II in the CETP-deficient heterozygote were not different from those in controls. These data establish that homozygous CETP deficiency causes markedly delayed catabolism of apoA-I and apoA-II without affecting the production rates of these apolipoproteins.

Adult↗