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Biomedical subjects

D Schumacher

Publications and source records attributed to D Schumacher.

At least 19 recordsLinked to original sources
PubMed2006

A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion.

OBJECTIVE: To compare changes in weight in obese patients who received long-acting octreotide (octreotide LAR) at one of three dose levels (20, 40, or 60 mg) or placebo over 6 months and to identify the lowest dose of octreotide LAR that safely achieved optimal weight loss. DESIGN: Randomized, double-blind, placebo-controlled trial of octreotide LAR at three dose levels. PATIENTS: A total of 172 adults (28 men and 144 women) with at least moderate obesity (body mass index (BMI) range 30-65 kg/m2) and evidence of insulin hypersecretion were enrolled. Patients were predominantly either Caucasian (50.0%) or African American (45.3%). The mean age (38 +/- 11 year), weight (110.7 +/- 23 kg), and BMI (39.8 +/- 6.5 kg/m2) were similar across the four treatment groups. MEASUREMENTS: Efficacy measures included weight, BMI, fasting serum glucose; triglycerides; percentage of total body fat and abdominal fat as measured by dual-energy X-ray absorptiometry; skin fold thickness; waist-to-hip circumference; leptin; percentage of carbohydrates, fat, and protein ingested; nutritional evaluation (including dietary analysis--3-day food record); quality of life (QoL; using the Impact of Weight on Quality of Life-Lite); Beck Depression Inventory; and Carbohydrate Craving Questionnaire. Safety measures included medical history, vital signs, physical examinations, hematology, blood chemistries, thyroid function tests, hemoglobin A1c, gallbladder ultrasound, electrocardiograms, and adverse events. RESULTS: After 6 months of treatment, patients receiving 40 or 60 mg of octreotide LAR experienced statistically significant weight loss compared to baseline, with mean differences from placebo in percent weight change of -1.98 and -1.87%, respectively. This finding was accompanied by statistically significant mean decreases in BMI compared to baseline, that is, a mean decrease of 0.73 and 0.79 kg/m2 for the 40 and 60 mg treatment arms, respectively. The observed weight loss was progressive during the 6-month treatment in the two higher dose groups. The lowest dose to reach statistical significance in weight loss after 6 months' treatment was 40 mg. Post hoc analysis revealed a 3.5-3.8% weight loss at month 6 in the two higher dose groups among Caucasian patients having insulin secretion greater than the median of the cohort, defined as CIR(gp) (corrected insulin response at the glucose peak) > or = 1.43. There were no statistically significant changes in QoL scores, body fat, leptin concentration, Beck Depression Inventory, or macronutrient intake. Mean changes of blood glucose AUC(0-180 min) during an oral glucose tolerance test in patients taking octreotide LAR were 39-40 mg/dl h higher than those on placebo. A total of 7-21% of the patients taking octreotide LAR reached a 5% or greater decrease in body weight from Baseline, compared to 11% for the placebo group. This was not statistically significant. The most common adverse events included diarrhea, headache, cholelithiasis, nausea, and abdominal pain. CONCLUSION: Octreotide LAR given at 40 or 60 mg resulted in statistically significant weight loss. A post hoc analysis stratifying patients by race and CIR(gp) indicated that Caucasian patients with the greater degree of insulin hypersecretion appeared to derive the most benefit from treatment. The observed safety profile was consistent with the known effects of octreotide from previous studies.

Adult↗
PubMed2004

Formation and stability of high-spin alkali clusters.

Helium nanodroplet isolation has been applied to agglomerate alkali clusters at temperatures of 380 mK. The very weak binding to the surface of the droplets allows a selection of only weakly bound, high-spin states. Here we show that larger clusters of alkali atoms in high-spin states can be formed. The lack of strong bonds from pairing electrons makes these systems nonmetallic, van der Waals-like complexes of metal atoms. We find that sodium and potassium readily form such clusters containing up to 25 atoms. In contrast, this process is suppressed for rubidium and cesium. Apparently, for these heavy alkalis, larger high-spin aggregates are not stable and depolarize spontaneously upon cluster formation.

Journal Article↗
PubMed2001

Interferometric pump-probe study of intense field excitation of sapphire.

Under intense optical excitation, the polarizability of transparent optical materials has a significant third order, nonlinear contribution. This manifests itself in a wide variety of effects, which, under certain conditions, are collectively referred to as white light continuum generation. We report on a new approach that isolates, for the first time, some of these effects.

Journal Article↗
PubMed2001

Chronic inborn erythrocytosis leads to cardiac dysfunction and premature death in mice overexpressing erythropoietin.

The most common cause of an increase of the hematocrit is secondary to elevated erythropoietin levels. Erythrocytosis is assumed to cause higher blood viscosity that could put the cardiovascular system at hemodynamic and rheological risks. Secondary erythrocytosis results from tissue hypoxia, and one can hardly define what cardiovascular consequences are caused by chronic erythrocytosis or hypoxia. Herein, a novel transgenic (tg) mouse line is characterized that is erythrocytotic because of chronic overexpression of the human erythropoietin gene. These mice grow up well, reaching a hematocrit of about 0.80 in adulthood. Blood volume of adult tg mice was markedly increased by 75%. Unexpectedly, blood pressure was not elevated and cardiac output was not decreased. Still, the adult tg mice showed features of cardiac dysfunction with increased heart weight. In vivo, high-frequency echocardiography revealed marked ventricular dilatation that was confirmed by histologic examination. Furthermore, by transmission electron microscopy, a prominent intracellular edema of the cardiomyocytes was seen. Exercise performance of the tg mice was dramatically reduced, unmasking the severity of their compromised cardiovascular function. In addition, life expectancy of the tg mice was significantly reduced to 7.4 months. Our findings suggest that severe erythrocytosis per se results in cardiac dysfunction and markedly reduced life span.

Age Factors↗
PubMed2001

Glycoproteins E and I of Marek's disease virus serotype 1 are essential for virus growth in cultured cells.

The role of glycoprotein E (gE) and gI of Marek's disease virus serotype 1 (MDV-1) for growth in cultured cells was investigated. MDV-1 mutants lacking either gE (20DeltagE), gI (20DeltagI), or both gE and gI (20DeltagEI) were constructed by recE/T-mediated mutagenesis of a recently established infectious bacterial artificial chromosome (BAC) clone of MDV-1 (D. Schumacher, B. K. Tischer, W. Fuchs, and N. Osterrieder, J. Virol. 74:11088-11098, 2000). Deletion of either gE or gI, which form a complex in MDV-1-infected cells, resulted in the production of virus progeny that were unable to spread from cell to cell in either chicken embryo fibroblasts or quail muscle cells. This was reflected by the absence of virus plaques and the detection of only single infected cells after transfection, even after coseeding of transfected cells with uninfected cells. In contrast, growth of rescuant viruses, in which the deleted glycoprotein genes were reinserted by homologous recombination, was indistinguishable from that of parental BAC20 virus. In addition, the 20DeltagE mutant virus was able to spread from cell to cell when cotransfected into chicken embryo fibroblasts with an expression plasmid encoding MDV-1 gE, and the 20DeltagI mutant virus exhibited cell-to-cell spread capability after cotransfection with a gI expression plasmid. The 20DeltagEI mutant virus, however, was not able to spread in the presence of either a gE or gI expression plasmid, and only single infected cells were detected by indirect immunofluorescence. The results reported here demonstrate for the first time that both gE and gI are absolutely essential for cell-to-cell spread of a member of the Alphaherpesvirinae.

Animals↗
PubMed2001

The selection of a commercial route for the D1 antagonist Sch-39166.

D1 Antagonists have been reported to be potentially useful in a number of therapeutic areas. Sch-39166 is an example of such a selective D1 antagonist. Three different routes based on (1S,2S)-1-phenyl-1,3-propanediol (19), (+)-L-homophenylalanine (27) or trans-(+)-(1R,2R)-2-hydroxy-1-(methylamino)-1,2,3,4-tetrahydronaphthalene (37) were developed for the commercial preparation of Sch-39166. After analyzing each route for the best combination of cost, yield, throughput and efficiency, the synthesis of Sch-39166 starting from 37, which involves the opening of an aziridinium, was selected for optimization into the commercial route.

Benzazepines↗
PubMed2000

Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine.

CONTEXT: Fenfluramine and dexfenfluramine were voluntarily withdrawn from the market in September 1997 because of reports of an association with heart valve abnormalities. Studies have been limited by lack of comparison with untreated controls. OBJECTIVE: To evaluate cardiovascular status and the prevalence of valvular abnormalities, as assessed by clinical cardiovascular parameters and echocardiography, in patients treated for obesity with dexfenfluramine or phentermine/fenfluramine. DESIGN: Reader-blinded controlled study completed in February 1998. SETTING AND PARTICIPANTS: Twenty-five clinical centers in the United States. Of 1640 enrolled subjects, 1473 were eligible (479 and 455 had taken dexfenfluramine and phentermine/fenfluramine, respectively, continuously for 30 days or more in the previous 14 months, and 539 were untreated matched controls) and provided clinical and echocardiographic data. Mean (SD) age was 47.4 (11.4) years, mean body mass index was 35.0 (7.4) kg/m2, and 74% were women. Mean (SD) duration of therapy was 6.0 (3.3) months (range, 1-18.4 months) in the dexfenfluramine group, and 11.9 (10.4) months (range, 1.4-63 months) in the phentermine/fenfluramine group, while the untreated group had no anorexigen use during the previous 5 years. MAIN OUTCOME MEASURES: Cardiovascular signs and symptoms; echocardiographic evidence of aortic (AR) or mitral (MR) regurgitation according to US Food and Drug Administration (FDA) criteria (AR > or = mild or MR > or = moderate) and by grade; tricuspid and pulmonic valve regurgitation; and aortic, mitral, and tricuspid valve leaflet mobility and thickness, for treated vs untreated subjects. RESULTS: Cardiovascular signs and symptoms were similar among anorexigen-treated and untreated subjects. Prevalence rates and relative risk (RR) of AR were significantly increased in anorexigen-treated patients and were 8.9% in the dexfenfluramine group (RR, 2.18; 95% confidence interval [CI], 1.32-3.59), 13.7% in the phentermine/fenfluramine group (RR, 3.34; 95% CI, 2.09-5.35), and 4.1% in the untreated group (P<.001). No statistically significant differences in prevalence were observed for MR, thickening or decreased mobility of any valve leaflet, calculated pulmonary artery systolic pressure, or left ventricular ejection fraction. Serious cardiac events (including myocardial infarction, congestive heart failure, or ventricular arrhythmia) occurring at any time were not statistically different in treated and untreated subjects (dexfenfluramine, 9.0%; phentermine/fenfluramine, 4.0%; and untreated, 8.4%); and following anorexigen treatment were uncommon (dexfenfluramine, 2.3%; phentermine/fenfluramine, 2.4%, and untreated, 3.3%, when adjusted for the median start date of anorexigen use). CONCLUSIONS: Our data indicate that use of dexfenfluramine and phentermine/fenfluramine is associated with an increase in the prevalence of AR using FDA echocardiographic criteria, but was not associated with an increase in the prevalence of MR using FDA criteria or with serious cardiac events.

Aortic Valve Insufficiency↗
PubMed2000

Reconstitution of Marek's disease virus serotype 1 (MDV-1) from DNA cloned as a bacterial artificial chromosome and characterization of a glycoprotein B-negative MDV-1 mutant.

The complete genome of Marek's disease virus serotype 1 (MDV-1) strain 584Ap80C was cloned in Escherichia coli as a bacterial artificial chromosome (BAC). BAC vector sequences were introduced into the U(S)2 locus of the MDV-1 genome by homologous recombination. Viral DNA containing the BAC vector was used to transform Escherichia coli strain DH10B, and several colonies harboring the complete MDV-1 genome as an F plasmid (MDV-1 BACs) were identified. DNA from various MDV-1 BACs was transfected into chicken embryo fibroblasts, and from 3 days after transfection, infectious MDV-1 was obtained. Growth of MDV-1 recovered from BACs was indistinguishable from that of the parental virus, as assessed by plaque formation and determination of growth curves. In one of the MDV-1 BAC clones, sequences encoding glycoprotein B (gB) were deleted by one-step mutagenesis using a linear DNA fragment amplified by PCR. Mutant MDV-1 recovered after transfection of BAC DNA that harbored a 2.0-kbp deletion of the 2.6-kbp gB gene were able to grow and induce MDV-1-specific plaques only on cells providing MDV-1 gB in trans. The gB-negative virus reported here represents the first MDV-1 mutant with a deletion of an essential gene and demonstrates the power and usefulness of BACs to analyze genes and gene products in slowly growing and strictly cell-associated herpesviruses.

Animals↗
PubMed1999

Initial weight loss as a predictor of response to obesity drugs.

BACKGROUND: Initial weight loss has been used as a predictor of long-term response to obesity drugs. Discontinuation of drugs has been recommended if weight loss is not > or =1.81 kg (4 lb) in the first month of treatment. OBJECTIVE: We compared the weight loss response at 6 months of patients losing > or =1.81 kg (responders) vs. < 1.81 kg (non-responders) in the first month of treatment with the combination of fenfluramine and phentermine. DESIGN: Outcomes at 6 months in 975 patients treated in a comprehensive program of phentermine (15-30 mg/d) d,l-fenfluramine (20-60 mg/d), were compared for responders vs. non-responders. RESULTS: In the total population, first month weight loss highly correlated with % reduction in body mass index (BMI) after 6 months of treatment (P<0.001). The reduction in baseline BMI after 6 months treatment was greater for the responders (15.9% vs. 10%, P<0.02). However, the North American Association for the Study of Obesity (NAASO) guidelines for drug treatment of obesity state that a 5% weight loss produces significant health benefits, and may be used as a criteria for success. At 6 months, 76%, 37% and 14% of the non-respondents had lost > or = 5%, > or = 10% and > or = 15% of baseline BMI, respectively. After 6 months treatment the reductions in serum cholesterol, triglycerides and LDL-cholesterol were 0.55, 0.31 and 0.42 mmol/L, respectively, (P< or =0.006), for the non-responders. Adverse effects after 6 months of treatment and the dropout rates after 1 y of treatment were not significantly different for the two groups. CONCLUSIONS: Although, the first month weight loss predicted the long-term response to phen-fen treatment, it was inadequate in identifying the non-responders and may unnecessarily preclude potential beneficiaries of the treatment.

Adult↗
PubMed1999

Ultrastructural localization of alpha-3 integrin subunit in malignant melanoma and adjacent epidermis.

Eight cases of malignant melanoma were studied by immunohistopathology and immunoelectron microscopy. Alpha3 integrin localization was documented in malignant melanoma cells, basal and suprabasal keratinocytes, melanocytes, blood vessels and in basement membrane material. In melanoma cell membranes and, to a lesser extent, the interior of melanosomal vesicles were labeled. In addition, neighbouring cells such as basal and suprabasal keratinocytes and melanocytes showed strong alpha3-integrin expression. The labeling was much stronger in the plasma membrane than in the cytoplasm. Endothelial cells showed stronger labeling of the cytoplasm than of the plasma membrane. In some cases we found increased flocculent material surrounding melanoma cells or nests that seems to contain basement membrane protein components, specifically alpha3-integrin subunits. Compared to normal epidermis alpha3-labeling was stronger in tissues of malignant melanoma.

Antigens, CD↗
PubMed1997

Long-term drug treatment of obesity in a private practice setting.

This study evaluated the long-term efficacy and safety of the combination of phentermine and fenfluramine for the treatment of obesity in a private practice setting. A total of 1388 consecutive, qualified patients presenting to a private general internal medicine practice in Charlotte, NC, were enrolled with eligibility criteria including: age 18 years to 60 years, 20% over "desirable" bodyweight or body mass index > 27, no serious medical or psychiatric disease, and no contraindications to drug therapy. Patients were instructed in diet, exercise, and behavior modification techniques and received phentermine (15 mg/day to 30 mg/day) and fenfluramine (20 mg/day to 60 mg/day) continuously for over 3 years. Average duration of treatment was 15.9 months, and average weight loss at the last visit was 11.6 kg, or 11.7% of initial bodyweight. For patients completing 1 year of drug treatment, mean weight loss was 16.5 kg, or 16% of initial weight. Weight loss persisted for 2 years, but partial regain was seen at 3 years. The dropout rates were 18% at 6 months, 39% at 1 year, 68% at 2 years, and 78% at 3 years. At 1 year, blood pressure of hypertensive patients fell from 151/95 mm Hg to 127/78 mm Hg, and serum cholesterol and triglycerides of hyperlipidemic patient fell by 0.750 mmol/L (29 mg/dL) and 0.937 mmol/L (83 mg/dL), respectively. Adverse events were modest. We conclude that, in a private practice setting, long-term treatment of obesity with the combination of phentermine, fenfluramine, and a weight maintenance program is generally safe and effective. More research is needed to determine efficacy and safety for longer than 3 years.

Adolescent↗
PubMed1996

In vivo diode dosimetry for total marrow irradiation.

PURPOSE: To describe a method and evaluate the efficacy of using a p-type silicon diode as an alternative to thermoluminescent dosimeters for verifying the accuracy of total marrow irradiation setups and calculations. METHODS AND MATERIALS: A calibration factor has been measured for a 6 MV photon beam incident horizontally onto a polystyrene phantom inside an in-house built total marrow irradiation stand. Signal responses due to positioning and orientation of the diode with respect to the source were compared to a 0.6 cc cylindrical ionization chamber inside a polystyrene phantom. Procedures for predicting the diode reading and taking entrance measurements have been developed and action levels established to determine causes for discrepancies when ratios between predicted and actual values fell outside a +/- 5% tolerance range. Measurements were taken at the skin surface over the umbilicus calculation point for alternating 1.5 Gy anterior and posterior fractions given bidaily over a 3-day period. RESULTS: A total of 137 measurements taken from January to September 1994 for 23 patients were analyzed using a frequency histogram. The histogram indicated a mean reading of 1.002 +/- 2.6, and that three of the measurements fell outside the 5% tolerance. Investigation into the cause of the discrepancies showed that the diode had been improperly placed one time and that further patient immobilization needs to be considered. CONCLUSION: It is possible to use a diode as an in vivo dosimeter for a total marrow irradiation technique. The ease of implementation and immediate readouts make a diode system preferable to a thermoluminescent system for identifying systematic errors and verifying treatment configurations and monitor unit calculations.

Bone Marrow↗
PubMed1996

[Degradation of Maillard reaction products by amylolytic enzymes. 2. Enzymatic degradation of heat-treated alpha-glucans with and without amino compounds].

The enzymatic degradation of thermal treated alpha-glucans with amylolytic enzymes depends on the reaction environment (T, pH, moisture), the degree of polymerisation (DP) and the branch of the substrates as well as on the presence of amino compounds. The chemical changes of the alpha-glucans due to thermolysis at 180 degrees C are characterized by means of the amount of reducing substances and the amount of maltooligosaccharides (HPLC). In general the enzymatic degradability of the thermal treated alpha-glucans is decreased with increasing time of thermolysis, temperature and moisture content. The enzyme activity with the thermal treated alpha-glucans is diminished in the same way. The addition of amino compounds reduces the enzymatic degradability only at the beginning of the reaction. With increasing time of thermolysis the thermolysates without glycine addition are hardly degraded. As reason for these differences in the enzymatic degradation transglycosylation and non-enzymatic browning reactions (caramalisation/Maillard-reaction) are assumed.

Chromatography, High Pressure Liquid↗
PubMed1996

[Degradation of Maillard reaction products by amylolytic enzymes. 3. Inhibition of glucoamylase, alpha-amylase and alpha-glucosidase by heat treated alpha-glucans and melanoidins].

Amylolytic enzymes are only slightly inhibited by thermal treated alpha-glucans (10-15%). The addition of glycine to the thermolysis mixture produces no increase of the inhibition. The inhibition of the enzyme activity is probably caused by short-chain alpha-glucans that the secondary binding places of the active centre coat and therefore the hydrolysis is reduced. Glucoamylase and alpha-amylase are not inhibited by non-dialysed melanoidines from the reaction of D-glucose and glycine, but there is a strong inhibition of alpha-glucosidase by these melanoidines (up to 45%). Strongly coloured, low molecular compounds that are formed during the Maillard-reaction and are soluble in ethyl acetate cause no inhibition of Glucoamylase and alpha-amylase.

Glucan 1,4-alpha-Glucosidase↗
PubMed1996

[The effect of Maillard reaction products on enzyme reactions].

In this article current knowledge about the Maillard reaction in vivo is described first, especially the glycosylation reactions of various tissues and the identification of different final products and intermediates of Maillard reaction. The influence of MRP on digestion is of significant importance. These products are absorbed in different ways and are excreted in various amounts. Hence, the organism is variably influenced by MRP. The influence of defined MRP, of glycosylated proteins and of melanoidins on glycosidases and proteases is described. The effects produced depend on the enzyme and on the used MRP. Reactive alpha-dicarbonyl compounds play an important role in the organism. Further possible reactions of these compounds caused by reductases are discussed. The protein structure of enzymes is changed by Maillard reaction. Thereby the enzyme activity is influenced by covalent modifications of different amino acids and by inter- and intramolecular crosslinking. Finally, the use of enzymes and monoclonal antibodies for detection of MRP is discussed.

Animals↗
PubMed1995

Combined drug treatment of obesity.

Pharmacological treatment of obesity has been neglected as a viable therapeutic option for many years. Recent long term studies with combinations of obesity drugs gives promise that drugs may play a role in weight maintenance, which classically has been the most difficult aspect of treating obesity. Currently available obesity drugs include centrally acting adrenergic agents and serotonin agonists. Drugs still in development include a lipase inhibitor that produces fat malabsorption, a combined adrenergic-serotonergic reuptake inhibitor, various gut-central nervous system peptides, and a number of beta-3 agonists. Any of these obesity drugs given alone produces modest weight loss, and for most, weight loss continues for as long as medication is given. The most successful drug regimens to date are combinations of phentermine and fenfluramine or of ephedrine, caffeine, and/or aspirin. The former combination produces reduction in body weight and complications of obesity for 2 to almost 4 years in clinical trials to date. More research is needed to document long term efficacy and particularly the long term safety of these and other combinations.

Adrenergic Agents↗
PubMed1994

[The decomposition of Maillard reaction products by amylolytic enzymes. 1. Reversible inhibition of alpha- and glucoamylase and alpha-glucosidase by oligosaccharide Amidori compounds].

The influence of Amadori-compounds (fructosyl-, maltulosyl- and maltotriulosylglycin) on the activity of the enzymes alpha-glucosidase (from Saccharomyces cerevisiae), glucoamylase (from Aspergillus niger) and alpha-amylase (from porcine pancreas) was studied. Fructosylglycin was not hydrolyzed by all three enzymes. alpha-Glucosidase hydrolyzes maltulosylglycin 10 times slower than maltotriulosylglycin. Glucoamylase and alpha-amylase catalyze only the cleavage of maltotriulosylglycin to form glucose and maltulosylglycin. The activities of alpha-glucosidase and glucoamylase are inhibited through the Amadori-compounds fructosyl- and maltulosylglycin. These Amadori-compounds don't influence the activity of alpha-amylase. Electronic effects or interactions between the secondary amino function of Amadori-compounds and the carboxyl- or carboxylate groups of active centres could be responsible for such an inhibition.

Animals↗