Biomedical subjects

Thomas Hofmann

Publications and source records attributed to Thomas Hofmann.

68 records · Page 4Linked to original sources

PubMed2003

Use of subcutaneous enoxaparin compared to intravenous heparin and oral phenprocoumon in the setting of cardioversion--the ACE study (Anticoagulation in Cardioversion using Enoxaparin).

The mode and duration of anticoagulation in the setting of cardioversion of atrial fibrillation-either with or without guidance by transesophageal echocardiography (TEE)-is still an unresolved issue. Oral anticoagulation with warfarin or phenprocoumon is frequently used but may be associated with an increased risk of bleeding complications or, conversely, episodes of undercoagulation. Moreover, it takes several days to reach full anticoagulation with oral compounds. This phase may be covered with intravenous heparin but this requires prolonged hospitalization. Low-molecular weight heparin is an attractive alternative as it not only provides a safe and predictable level of anticoagulation with few side effects but can also be administered safely on an outpatient basis. In addition, anticoagulation monitoring is usually unnecessary. The ACE study (Anticoagulation in Cardioversion using Enoxaparin) compared the safety and efficacy of subcutaneous enoxaparin with intravenous heparin/oral phenprocoumon before and after cardioversion (stratified to TEE guidance or no TEE guidance). This article summarizes the study rationale and design. The results will be published shortly.

Administration, Oral↗

PubMed2003

Effects of a diet rich in advanced glycation end products in the rat remnant kidney model.

BACKGROUND: Food-derived advanced glycation end product (AGE)-analogues, the Maillard reaction products (MRPs), are formed during heat processing. Mainly low molecular weight MRPs are absorbed partially into the circulation and subsequently excreted in urine. In the presence of renal insufficiency, their removal is impaired, with a prolonged increase in plasma levels. Although bioactivity of orally absorbed MRPs has been shown in both experimental and human studies, its relevance in renal insufficiency still is unclear. METHODS: In the rat remnant-kidney model (five-sixth nephrectomy [5/6NX]), effects of an AGE-rich and an AGE-poor diet were investigated during a period of 6 weeks and compared with effects in sham-operated healthy (control [CTRL]) rats on renal function (serum creatinine level and proteinuria). In the AGE-rich diet, 25% wt/wt of cornstarch was replaced by bread crusts. RESULTS: Despite pair feeding, the AGE-rich diet resulted in a significant increase in body weight, including weight of the kidney, liver, and heart, in both the CTRL and experimental groups. The AGE-rich diet also enhanced proteinuria in CTRL rats by a factor of 2 and in 5/6NX rats by a factor of 8. Renal function (serum creatinine level and creatinine clearance) in healthy CTRLs did not change significantly. In the 5/6NX group, glomerular filtration rate (GFR) tended to even higher levels. CONCLUSION: Administration of an AGE-rich diet for 6 weeks does not impair GFR, but induces an increase in proteinuria, in particular, in the 5/6NX rats, indicating detrimental effects on the kidney.

Animals↗

PubMed2003

(+)-(S)-alapyridaine--a general taste enhancer?

N-(1-Carboxyethyl)-6-hydroxymethyl-pyridinium-3-ol inner salt (alapyridaine), recently identified in heated sugar/amino acid mixtures as well as in beef bouillon, has been shown to exhibit general taste-enhancing activities, although tasteless on its own. Differing from other taste enhancers reported so far, racemic (R/S)-alapyridaine and, to an even greater extent (+)-(S)-alapyridaine, the physiologically active enantiomer, are able to enhance more than one basic taste quality. The threshold concentrations for the sweet taste of glucose and sucrose, for the umami taste of monosodium L-glutamate (MSG) and guanosine-5'-monophosphate (GMP), as well as the salty taste of NaCl, were significantly decreased when alapyridaine was present. In contrast, perception of the bitter tastes of caffeine and L-phenylalanine, as well as of sour-tasting citric acid, was unaffected. Furthermore, alapyridaine was shown to intensify known taste synergies such as, for example, the enhancing effect of L-arginine on the salty taste of NaCl, as well as that of GMP on the umami taste of MSG. The activity of (+)-(S)-alapyridaine could be observed not only in solutions of single taste compounds, but also in more complex tastant mixtures; for example, the umami, sweet and salty taste of a solution containing MSG, sucrose, NaCl and caffeine was significantly modulated, thus indicating that alapyridaine is a general taste enhancer.

Adult↗

PubMed2003

Disseminated tumor cells in bone marrow of patients with transitional cell carcinoma: immunocytochemical detection and correlation with established prognostic indicators.

PURPOSE: Previous investigations have demonstrated the prognostic value of disseminated cytokeratin positive cells in bone marrow of patients with breast, gastric, colon and prostate cancer. We evaluated the potential of an immunocytochemical assay, using a monoclonal antibody against cytokeratin 18 (CK 18), for the detection of disseminated tumor cells in bone marrow aspirates of patients with transitional cell carcinoma. MATERIALS AND METHODS: Bone marrow aspiration was performed preoperatively on 128 patients with transitional cell carcinoma of various stages and on 27 controls with nonmalignant disease. Cytospin preparations of mononuclear bone marrow cells were incubated with a monoclonal anti-CK 18 antibody and stained using the alkaline phosphatase anti-alkaline phosphatase technique. RESULTS: Of the patients with transitional cell carcinoma 29.7% and none of the controls had a CK 18 positive bone marrow result. A significant correlation between the incidence of CK 18 positive cells in bone marrow and invasive transitional cell carcinoma (p <0.01), lymph node involvement (p <0.01), medium/high grade transitional cell carcinoma (p <0.01) and tumor progression in recurrent transitional cell carcinoma (p <0.05) was demonstrated. Furthermore, the mean number of CK 18 positive cells in bone marrow aspirates of patients with stage M+ and/or N+ disease was nearly 3 times as high as that of patients without clinically evident metastatic disease (10.4 versus 3.8 CK 18 positive cells per patient). CONCLUSIONS: A significant correlation between the incidence of CK 18 positive bone marrow results in patients with transitional cell carcinoma and established risk factors could be demonstrated in our study. Further prospective followup studies should be performed to determine the prognostic value of these findings.

Aged↗

PubMed2002

Structural and functional characterization of pronyl-lysine, a novel protein modification in bread crust melanoidins showing in vitro antioxidative and phase I/II enzyme modulating activity.

Application of an in vitro antioxidant assay to solvent fractions isolated from bread crust, bread crumb, and flour, respectively, revealed the highest antioxidative potential for the dark brown, ethanol solubles of the crust, whereas corresponding crumb and flour fractions showed only minor activities. To investigate whether these browning products may also act as antioxidants in biological systems, their modulating activity on detoxification enzymes was investigated as a functional parameter in intestinal Caco-2 cells. The bread crust and, in particular, the intensely brown, ethanolic crust fraction induced a significantly elevated glutathione S-transferase (GST) activity and a decreased phase I NADPH-cytochrome c reductase (CCR) activity compared to crumb-exposed cells. Antioxidant screening of Maillard-type model mixtures, followed by structure determination, revealed the pyrrolinone reductones 1 and 2 as the key antioxidants formed from the hexose-derived acetylformoin and N(alpha)-acetyl-L-lysine methyl ester or glycine methyl ester, chosen as model substances to mimic nonenzymatic browning reactions with the lysine side chain or the N terminus of proteins, respectively. Quantitation of protein-bound pyrrolinone reductonyl-lysine, abbreviated pronyl-lysine, revealed high amounts in the bread crust (62.2 mg/kg), low amounts in the crumb (8.0 mg/kg), and the absence of this compound in untreated flour. Exposing Caco-2 cells for 48 h to either synthetically pronylated albumin or purified pronyl-glycine (3) significantly increased phase II GST activity by 12 or 34%, respectively, thus demonstrating for the first time that "pronylated" proteins as part of bread crust melanoidins act as monofunctional inducers of GST, serving as a functional parameter of an antioxidant, chemopreventive activity in vitro.

Antioxidants↗

PubMed2002

The human TAS2R16 receptor mediates bitter taste in response to beta-glucopyranosides.

Bitter taste generally causes aversion, which protects humans from ingesting toxic substances. But bitter flavors also contribute to the palatability of food and beverages, thereby influencing nutritional habits in humans. Although many studies have examined bitter taste, the underlying receptor mechanisms remain poorly understood. Anatomical, functional and genetic data from rodents suggest the existence of a family of receptors that are responsive to bitter compounds. Here we report that a human member of this family, TAS2R16, is present in taste receptor cells on the tongue and is activated by bitter beta-glucopyranosides. Responses to these phytonutrients show a similar concentration dependence and desensitization in transfected cells and in experiments assessing taste perception in humans. Bitter compounds consisting of a hydrophobic residue attached to glucose by a beta-glycosidic bond activate TAS2R16. Thus, TAS2R16 links the recognition of a specific chemical structure to the perception of bitter taste. If the ability of TAS2R16 to detect substances with common molecular properties is typical of the bitter receptor family, it may explain how a few receptors permit the perception of numerous bitter substances.

Benzyl Alcohols↗

PubMed2002

Reinvestigation of the chemical structure of bitter-tasting quinizolate and homoquinizolate and studies on their Maillard-type formation pathways using suitable (13)C-labeling experiments.

Very recently, application of taste dilution analysis to heated xylose/alanine solutions led to the isolation of two bitter-tasting compounds exhibiting extraordinarily low detection thresholds of 0.00025 and 0.001 mmol/kg of water, respectively. On the basis of LC-MS and NMR spectroscopy, the structures of these compounds, named quinizolate and homoquinizolate, were proposed as 1-oxo-1H,4H-quinolizinium-7-olates. Since recent experiments in our laboratory shed some doubt on the entire correctness of their structures, labeling experiments with mixtures of multiply (13)C-labeled and nonlabeled pentoses were performed to follow the joint transfer of several (13)C atoms en bloc into the bitter compounds by LC-MS and NMR isotopomer diagnosis. The site-specific visualization of the mosaics assembled from (13)C-labeled and (12)C-labeled carbon modules in both bitter compounds demonstrated the structures of quinizolate and homoquinizolate to be the previously unknown (2E)-7-(2-furylmethyl)-2-(2-furylmethylidene)-3-(hydroxymethyl)- and (2E)-7-(2-furylmethyl)-2-(2-furylmethylidene)-3,8-bis(hydroxymethyl)-1-oxo-2,3-dihydro-1H-indolizinium-6-olate.

Carbon Isotopes↗

PubMed2002

Quantitative model studies on the efficiency of precursors in the formation of cooling-active 1-pyrrolidinyl-2-cyclopenten-1-ones and bitter-tasting cyclopenta-[b]azepin-8(1H)-ones.

The yields of the cooling-active compounds 3-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (1) and 5-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (2) as well as the bitter tastants 7-methyl-2,3,6,7-tetrahydrocyclopenta-[b]azepin-8(1H)-one (3) and 7-methyl-2,3,4,5,6,7-hexahydrocyclopenta-[b]azepin-8(1H)-one (4) obtained by heating mixtures of possible Maillard-type precursors in model systems varying in temperature, pH value, or water content were determined quantitatively. The results showed that hexose-derived cyclotene is the common precursor for all four tastants and that the formation of each individual tastant is strongly determined by the structure of the nitrogen-containing precursor, e.g., reaction of cyclotene with pyrrolidine formed by thermal decarboxylation of L-proline produced the cooling compounds 1 and 2 only, whereas in the presence of 1-pyrroline formed upon Strecker reactions of L-proline, the bitter tasting azepinone 3 was produced exclusively. In contrast, the structure of the secondary amino acid L-proline enabled the formation of compound 4, whereas the pyrrolidine and 1-pyrroline, respectively, do not generate this tastant. In addition, a nonvolatile, tasteless intermediate, (S)-3-methyl-2-[(2'-carboxy)-1-pyrrolidinyl]-2-cyclopenten-1-one (5), was isolated from the cyclotene/L-proline reaction mixture and could be confirmed as an efficient precursor for the cooling compound 1. The data, obtained by these studies, are the scientific basis to tailor the desired overall flavor of foods by means of a more controlled Maillard-type technology.

Amino Acids↗

PubMed2002

Subunit composition of mammalian transient receptor potential channels in living cells.

Hormones, neurotransmitters, and growth factors give rise to calcium entry via receptor-activated cation channels that are activated downstream of phospholipase C activity. Members of the transient receptor potential channel (TRPC) family have been characterized as molecular substrates mediating receptor-activated cation influx. TRPC channels are assumed to be composed of multiple TRPC proteins. However, the cellular principles governing the assembly of TRPC proteins into homo- or heteromeric ion channels still remain elusive. By pursuing four independent experimental approaches--i.e., subcellular cotrafficking of TRPC subunits, differential functional suppression by dominant-negative subunits, fluorescence resonance energy transfer between labeled TRPC subunits, and coimmunoprecipitation--we investigate the combinatorial rules of TRPC assembly. Our data show that (i) TRPC2 does not interact with any known TRPC protein and (ii) TRPC1 has the ability to form channel complexes together with TRPC4 and TRPC5. (iii) All other TRPCs exclusively assemble into homo- or heterotetramers within the confines of TRPC subfamilies--e.g., TRPC4/5 or TRPC3/6/7. The principles of TRPC channel formation offer the conceptual framework to assess the physiological role of distinct TRPC proteins in living cells.

Calcium Channels↗

PubMed2002

Chemical interactions between odor-active thiols and melanoidins involved in the aroma staling of coffee beverages.

Comparative aroma dilution analyses of the headspaces of aqueous solutions containing either the total volatiles isolated from a fresh coffee brew, or these volatiles remixed with the melanoidins isolated from coffee brew, revealed a drastic decrease in the concentrations of the odorous thiols 2-furfurylthiol, 3-methyl-2-butenthiol, 3-mercapto-3-methylbutyl formate, 2-methyl-3-furanthiol, and methanethiol when melanoidins were present. Among these thiols, 2-furfurylthiol was affected the most: e.g., its concentration decreased by a factor of 16 upon addition of melanoidins. This was accompanied by a decrease in the overall roasty-sulfury aroma. Quantitations performed by means of stable isotope dilution assays confirmed the rapid loss of all thiols with increasing time while keeping the coffee brew warm in a thermos flask. Using [2H2]-2-furfurylthiol as an example, [2H]-NMR and LC/MS spectroscopy gave strong evidence that thiols are covalently bound to the coffee melanoidins via Maillard-derived pyrazinium compounds formed as oxidation products of 1,4-bis-(5-amino-5-carboxy-1-pentyl)pyrazinium radical cations (CROSSPY). Using synthetic 1,4-diethyl diquaternary pyrazinium ions and 2-furfurylthiol, it was shown that 2-(2-furyl)methylthio-1,4-dihydro-pyrazines, bis[2-(2-furyl)methylthio]-1,4-dihydro-pyrazines, and 2-(2-furyl)methylthio-hydroxy-1,4-dihydro-pyrazines were formed as the primary reaction products. Similar results were obtained for models in which either 1,4-diethyl diquaternary pyrazinium ions were substituted by Nalpha-acetyl-L-lysine/glycolaldehyde, or the 2-furfurylthiol by 2-methyl-3-furanthiol and 3-mercapto-3-methylbutyl formate. On the basis of these results it can be concluded that the CROSSPY-derived pyrazinium intermediates are involved in the rapid covalent binding of odorous thiols to melanoidins, and, consequently, are responsible for the decrease in the sulfury-roasty odor quality observed shortly after preparation of the coffee brew.

Binding Sites↗

PubMed2002

Predicting CNS permeability of drug molecules: comparison of neural network and support vector machine algorithms.

Two different machine-learning algorithms have been used to predict the blood-brain barrier permeability of different classes of molecules, to develop a method to predict the ability of drug compounds to penetrate the CNS. The first algorithm is based on a multilayer perceptron neural network and the second algorithm uses a support vector machine. Both algorithms are trained on an identical data set consisting of 179 CNS active molecules and 145 CNS inactive molecules. The training parameters include molecular weight, lipophilicity, hydrogen bonding, and other variables that govern the ability of a molecule to diffuse through a membrane. The results show that the support vector machine outperforms the neural network. Based on over 30 different validation sets, the SVM can predict up to 96% of the molecules correctly, averaging 81.5% over 30 test sets, which comprised of equal numbers of CNS positive and negative molecules. This is quite favorable when compared with the neural network's average performance of 75.7% with the same 30 test sets. The results of the SVM algorithm are very encouraging and suggest that a classification tool like this one will prove to be a valuable prediction approach.

Algorithms↗

PubMedDate not supplied

Harmonization of rat fetal external and visceral terminology and classification. Report of the Fourth Workshop on the Terminology in Developmental Toxicology, Berlin, 18-20 April 2002.

This article is a report on the Fourth Berlin Workshop on Terminology in Developmental Toxicology, which was held in April 2002. The workshop is part of an international project in the field of harmonization of terminology in developmental toxicology supported by IPCS. The goal of the Harmonization Project is to ensure better chemical risk assessment. The aim of this Fourth Workshop was to discuss the results of a previously conducted survey on classification of external and visceral anomalies, which are listed in the international glossary, developed under the auspices of IFTS (1997 glossary). The discussions among experts from research institutions, regulatory agencies, and industries were mainly focussed on terms for which there was disagreement and/or uncertainties and the possible reasons. For the illustration of "gray-zone" anomalies, pictures were provided by the participants, which constituted the basis for detailed discussions. There was high agreement that most of the external anomalies (>66%) should be classified as malformations. The few external anomalies for which there was low agreement to classify as a malformation were discussed in detail. None of the external findings, which had in the survey a high agreement, were categorized as a variation.A high agreement regarding the classification of approximately one-third of visceral anomalies was achieved with 34 and 2% being described as malformation and variation, respectively. Most of the visceral findings had low agreement indices and there appeared to be several reasons for this. Thus, the response, 'Not known/not used in the laboratory' (N) was often given. A couple of reasons for difficulties in the classification of an anomaly were that it is only rarely seen upon fetal examination or tends to be species specific. Furthermore, the classification of some anomalies as malformation or variation will remain vague as the decision must be made on a case-by-case basis. Factors affecting the decision include: the availability of appropriate historical control data, description of the grading and severity, whether the anomaly occurs in isolation or whether there is a relationship with an abnormal process, and finally, if the change represents an irreversible one, affecting human and/or animal health. It was concluded that a severity grading, supported by pictures of the anomaly, would be especially helpful to classify certain changes as malformation or as variation. Several of the soft tissue changes were considered likely to be the consequence of functional disorders and thus not strictly developmental anomalies. The possibility to describe a finding as 'Not Malformation' (Unclassified) was agreed upon. As a general conclusion it was emphasized that the observation of a permanent structural change should be considered to be a warning of possible consequences to humans, even when there is no apparent adverse effect on health and survival in adult animals of the species under investigation. Therefore, research is needed to further investigate postnatal consequences. Future collaboration in the field of reproductive and developmental toxicology should aim to further develop and implement a harmonized approach to the interpretation of study data. Therefore, this terminology work will continue in close cooperation with the IPCS Harmonization Project. A Steering Group should be established to facilitate the implementation of harmonized terminology into daily scientific work and its regulatory application.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Value of intravascular ultrasound for endovascular stent-graft placement in aortic dissection and aneurysm.

BACKGROUND: Endovascular stent-graft placement is a new concept for the treatment of aortic dissection and aneurysm. Intravascular ultrasound (IVUS) with established diagnostic features may be instrumental in guiding endovascular procedures. METHODS: We performed IVUS and digital angiography before, during, and after implantation of 47 stent grafts in 40 patients with Stanford type B dissection (26 patients, 28 stent grafts), thoracic aneurysm (9 patients, 11 stent grafts), and abdominal aneurysm (5 patients, 8 stent grafts). RESULTS: IVUS could clearly identify the aortic anatomy and differentiate between true and false lumen in all cases of dissection. In four patients with type B dissection extending from the thoracic to the abdominal aorta the true lumen was exclusively identified by IVUS, and thus, essential for safe execution of the procedure. In another patient stent-graft placement in the aorta was optimized by covering a second entry detected by IVUS, but undetected by angiography. The site of stent implantation, the true and false lumen, as well as entry and reentry were always identified in both thoracic and abdominal aorta. In comparison with angiography, IVUS information led to additional balloon molding due to incomplete stent apposition in seven cases. CONCLUSIONS: As an adjunctive imaging modality IVUS is likely to improve stent-graft placement in aortic type B dissection, especially in patients with abdominal extension.

Adult↗

PubMedDate not supplied

Evaluation of the reproductive toxicity and embryotoxicity of insulin glargine (LANTUS) in rats and rabbits.

Insulin glargine (LANTUS) is a new insulin analog that has a prolonged duration of action with no pronounced peak of activity, rendering it an ideal basal insulin for the treatment of diabetes. The aim of these studies was to assess the reproductive and embryotoxicity of insulin glargine. Reproductive toxicity was assessed in 25 male and 25 female Wistar rats per group treated with a daily subcutaneous injection of control; 1 IU/kg, 3 IU/kg, and 10 IU/kg insulin glargine; or 3 IU/kg NPH insulin in the premating and mating periods, and throughout pregnancy and lactation in the females. Embryotoxicity was assessed in 20 female rats per group injected with daily subcutaneous doses of control; 2 IU/kg, 6.3 IU/kg, and 20 IU/kg insulin glargine; or 6.3 IU/kg NPH insulin from the 7th to 18th day of pregnancy. Embryotoxicity was also assessed in 20 female rabbits per group treated with 0 IU/kg, 0.5 IU/kg, 1 IU/kg, and 2 IU/kg insulin glargine, or 1 IU/kg NPH insulin from the 6th to 18th day of pregnancy. The data demonstrated that, with the exception of toxicologic effects induced by hypoglycemia in response to high doses of insulin glargine and NPH insulin (including the premature dropout of female rats in the reproductive toxicity study, and increased incidence of abortions, early intrauterine deaths, and single anomalies in the rabbit embryotoxicity study), insulin glargine had no effects on reproduction, embryofetal development, and postnatal development in rats. Maternal and embryofetal toxicity in rabbits treated with middle and high doses of insulin glargine was related to the hypoglycemic effect of insulin.

Animals↗