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Biomedical subjects

D Mayer

Publications and source records attributed to D Mayer.

At least 163 records · Page 9Linked to original sources
PubMed1989

Individual gustatory reaction times to various groups of chemicals that provoke basic taste qualities.

Reaction times (RTs) to four groups of substances that provoke different taste qualities were measured. Measurements for all substances with the same taste, equalized in perceived intensity and provoking a very strong taste, were made concurrently for each subject. The comparisons were made on the individual level. No significant differences in RTs to substances with the same taste quality were found. When the factor of perceived intensity is kept constant, no effect of the stimulus chemical composition on RTs seems to be present. RTs to stimuli with different tastes differ significantly, the shortest being to salt and the longest to bitter. The difference in RTs for sour and sweet substances is small, and the subjects were not all alike in terms of the order of RTs with respect to these stimuli.

Humans↗
PubMed1989

Mechanism-based analysis of enzyme inhibitors of amide bond hydrolysis.

Biochemical information regarding the mechanism of amide bond hydrolysis offers insight into the possible chemical groups in the enzyme active site responsible for hydrolysis. Assuming that these groups have a relatively fixed geometry in accord with their functional role, then their three-dimensional position in space can be determined if sufficient structural diversity exists within the data set of compounds with known affinities. Each compound which binds can be augmented by additional chemical groups to represent the receptor's functional groups. For each compound, the set of geometrical arrangements of these groups which would show optimal binding to the compound can be determined by systematic search. A common geometric arrangement representing the active site geometry should be present for each compound. In studies of the binding of mechanism-based inhibitors of chymotrypsin, Naruto et al. (1985) showed some movement of active site residues to accommodate different ligands. Nevertheless, this procedure found a unique active site geometry for ACE which compared favorably with that of carboxypeptidase A, an enzyme of analogous function.

Amides↗
PubMed1989

Surgery for gastro-oesophageal reflux: the Angelchik prosthesis compared to the floppy Nissen fundoplication. Two-year follow-up study and a five-year evaluation of the Angelchik prosthesis.

Twenty-two patients were followed for 5 years after insertion of an Angelchik prosthesis for gastro-oesophageal reflux (GOR) and the 2-year results compared with a subsequent group of 28 patients treated by floppy Nissen fundoplication. The overall clinical results of the two procedures were equivalent at 2 years (Angelchik Visick 1 and 2, 80%; Nissen Visick 1 and 2, 78%) but the reasons for failure were different. In the Angelchik group failures were due to mechanical problems associated with the device, whereas the Nissen failures were mainly due to recurrent GOR. There were no patients in the Angelchik group with recurrent reflux at 5 years, but between 4 and 5 years postoperatively four patients developed mild dysphagia. The Angelchik prosthesis appears to be as effective as the floppy Nissen fundoplication, but further long-term studies are required before its widespread use can be recommended.

Adolescent↗
PubMed1988

Specific alterations of rat renal microsomal proteins induced by cephaloridine.

In order to elucidate the molecular mechanisms of cephaloridine (CPH) nephrotoxicity, the effect of cephaloridine treatment on the protein composition of different subcellular fractions from rat kidney cortex was investigated. After intravenous treatment of male Wistar rats with 250-1200 mg/kg/d CPH for 1-3 days, kidneys were removed and the homogenate from renal cortex was separated into lysosomal, cytosolic and microsomal fractions. The polypeptide composition of the different subfractions was analyzed by one-dimensional SDS-gel electrophoresis and quantified by densitometry. Significant differences in the polypeptide composition between treated and non-treated animals were seen in the microsomal fraction. CPH-treatment induced a polypeptide with an apparent molecular weight of 44,000 and decreased the content of cytochrome P-450 isoenzymes in the microsomal fraction. Solubilization experiments showed that the CPH-induced microsomal polypeptide of molecular weight 44,000 is a peripheral membrane protein rather than an integral membrane protein. The induction of this protein by CPH was dose- and time-dependent. Preliminary experiments using the kidney slice technique indicate that the induction of this polypeptide correlates with the nephrotoxicity measured as decrease in renal cortical accumulation of organic ions. Thus, the results of the present study indicate that treatment of rats with CPH resulted in the induction of a microsomal polypeptide of molecular weight 44,000 which could be a sensitive parameter of cephaloridine nephrotoxicity.

Animals↗
PubMed1988

Activity of glycogen synthase and phosphorylase and glucose 6-phosphate content in renal clear cell carcinomas.

Eleven renal clear cell carcinomas were investigated with regard to their glycogen and glucose 6-phosphate (G6P) content and the activities of glycogen synthase and phosphorylase. Compared to normal cortex from the same kidneys, all tumours revealed increased glycogen and G6P content. The activities of phosphorylase a and b as well as of synthase R and D were also increased. Synthase I activity, however, was reduced. It was concluded that in these tumours glycogen synthesis may preferentially be catalyzed by synthase R which is activated by G6P. These findings agree with those in some other glycogenotic tissues and support the concept that an accumulation of G6P is associated with excessive storage of glycogen in preneoplastic and neoplastic lesions.

Adenocarcinoma↗
PubMed1988

Dehydroepiandrosterone induced alterations in rat liver carbohydrate metabolism.

Long-term dietary administration of the adrenal hormone dehydroepiandrosterone (DHEA) to male Sprague-Dawley rats induced significant alterations in the activities of enzymes involved in liver carbohydrate metabolism. Although glycogen synthase activity was increased and phosphorylase decreased, glycogen stores were reduced. This was presumably related to lysosomal glycogen degradation, since alpha-glucosidase was increased. All rate-limiting enzymes of glucose metabolism which were studied (glucose-6-phosphate dehydrogenase, total hexokinases, pyruvate kinase, fructose-1,6-bisphosphatase) revealed markedly reduced activity, only glucose-6-phosphatase activity was increased. These enzymatic changes point to a far-reaching metabolic shift towards energy loss via decreased glucose consumption and increased glucose output. The enzyme pattern induced by DHEA is in many respects opposite to that induced in preneoplastic and neoplastic liver lesions by chemical hepatocarcinogens.

Animals↗
PubMed1988

Acute, subchronic and chronic toxicity of the new angiotensin converting enzyme inhibitor ramipril.

Acute, subchronic and chronic toxicity studies of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S, 3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (ramipril, Hoe 498) were conducted in mice, rats, dogs and monkeys. The acute toxicity in mice, rats, and dogs after oral and intravenous administration is very low. There were no significant differences in LD50 values between male and female animals. Treatment periods up to 6 months in rats and monkeys and up to 12 months in dogs revealed consistent compound-related effects with respect to the kidneys and the hemopoietic system probably due to exaggerated pharmacological activity. Species-specific lesions in the gastric fundal mucosa were noted exclusively in rats. No adverse effects were seen at doses of 0.25 mg/kg/d in rats, 2.5 mg/kg/d in dogs, and 0.5 mg/kg/d in monkeys. It is concluded that ramipril can be safely used in humans.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Transcription activation of the tyrosine aminotransferase gene by glucocorticoids and cAMP in primary hepatocytes.

The expression of the tyrosine aminotransferase (TAT) gene of the rat was analyzed in primary hepatocytes. The TAT gene remains active in primary cultured cells at a level similar to that in liver cells. Expression can be induced by glucocorticoids and cAMP, glucocorticoids lead to a 8-10-fold increase in TAT mRNA level, cAMP to a 20-30-fold increase. The elevation of the TAT mRNA is preceeded by a rise in the relative rate of transcription of the gene. Surprisingly transcription of the albumin gene, which steadily declines with the age of the culture, can also strongly be stimulated by glucocorticoids in primary hepatocytes. cAMP antagonists, which act as competitive inhibitors of the cAMP-dependent protein kinase, prevent induction of transcription of the tyrosine aminotransferase gene by cAMP suggesting that the effect of cAMP on expression of the tyrosine aminotransferase gene is mediated by a cAMP-dependent protein kinase. The cAMP antagonist does not interfere with induction by glucocorticoids which suggests that phosphorylation of the glucocorticoid receptor by the cAMP-dependent protein kinase is not required for its function. We thus conclude that the two inducers affect transcription by independent mechanisms.

Animals↗
PubMed1987

A unique geometry of the active site of angiotensin-converting enzyme consistent with structure-activity studies.

Previous structure-activity studies of captopril and related active angiotensin-converting enzyme (ACE) inhibitors have led to the conclusion that the basic structural requirements for inhibition of ACE involve (a) a terminal carboxyl group; (b) an amido carbonyl group; and (c) different types of effective zinc (Zn) ligand functional groups. Such structural requirements common to a set of compounds acting at the same receptor have been used to define a pharmacophoric pattern of atoms or groups of atoms mutually oriented in space that is necessary for ACE inhibition from a stereochemical point of view. A unique pharmacophore model (within the resolution of approximately 0.15 A) was observed using a method for systematic search of the conformational hyperspace available to the 28 structurally different molecules under study. The method does not assume a common molecular framework, and, therefore, allows comparison of different compounds that is independent of their absolute orientation. Consequently, by placing the carboxyl binding group, the binding site for amido carbonyl, and the Zn atom site in positions determined by ideal binding geometry with the inhibitors' functional groups, it was possible to clearly specify a geometry for the active site of ACE.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Expression and regulation of glycogen phosphorylase in preneoplastic and neoplastic hepatic lesions in rats.

Glycogen phosphorylase (PHO) was demonstrated immunocytochemically and enzyme histochemically in cryostat sections of liver from rats treated for 7 weeks with N-nitrosomorpholine (120 mg/l and 200 mg/l drinking water) and from untreated controls. The activity and distribution of PHO protein were studied in normal liver and correlated with morphologically defined stages of hepatic tumour development. In normal liver the amount of enzyme protein, as visualized by the immunoperoxidase method using antibodies against phosphorylase, showed some heterogeneity within the liver lobule. The intralobular and intracellular distribution of PHO protein was the same as that of glycogen, namely coarse and granular in periportal hepatocytes and very fine in perivenular cells. In glycogen storage foci the amount of PHO protein was increased. In contrast, PHO activity was generally decreased. In other preneoplastic and neoplastic lesions such as mixed cell foci, neoplastic nodules and hepatocellular carcinomas, PHO protein was increased in all glycogen-loaded cells while PHO activity was reduced. In all glycogen-poor and basophilic cells, both PHO protein and PHO activity were decreased or absent. It was concluded that the decrease in PHO activity in glycogen storage foci was not the direct consequence of genetic changes leading to a loss in enzyme protein but was due to a defect in the cascade of phosphorylation processes resulting in active PHO. Alteration in gene expression leading to a loss of PHO protein was a late event in the process of hepatocarcinogenesis.

Animals↗
PubMed1987

Investigations of the carcinogenicity of the LH-RH analog buserelin (HOE 766) in rats using the subcutaneous route of administration.

A carcinogenicity study with the LH-RH analog buserelin (HOE 766) was conducted in male and female Wistar rats. The compound was administered subcutaneously daily for a period of 24 months to groups of 50 male and 50 female animals in doses of 0.0002, 0.0006, or 0.0018 mg/kg body wt, followed by a 6-month recovery period without any treatment. Male and female rats (100 each) received physiological saline and served as controls. The body weight development of all male rats was regular, but in females at all three dose levels significantly increased body weight gain in comparison to the control animals occurred. Food consumption was not affected in any group. No treatment-related changes in clinical signs and hematological parameters were noted. The chronic administration of HOE 766 did not influence the survival of the male rats while in females it was dose-dependently increased. Endocrinological examinations revealed decreased serum testosterone levels in males and reduced serum progesterone levels in females during the treatment period; the changes reverted to normal during the recovery period. Reduced weights of the testes and uteri as well as increased weights of the pituitaries and ovaries in females are compound-related. Histological examination of the animals which died intercurrently or were killed in extremis or at the end of the recovery period revealed irreversible and partly dose-dependent changes in testes and uterus, due to the pharmacodynamic properties of HOE 766, but gave no indication of any carcinogenic effect of the compound.

Animals↗
PubMed1987

Sequential histochemical and morphometric studies on preneoplastic and neoplastic lesions induced in rat colon by 1,2-dimethylhydrazine.

The sequential histochemical changes during colon carcinogenesis were studied in male Sprague-Dawley rats given 16 weekly subcutaneous injections of 15 mg 1,2-dimethylhydrazine per kg body wt and serially killed at regular intervals. Cryostat sections were used to study the mucus content of the colonic mucosa with the periodic acid Schiff's reaction, and enzyme histochemical methods were applied to investigate the activity of some key enzymes of carbohydrate metabolism at different stages of carcinogenesis. Enlarged mucus-rich crypts with a marked hypercellularity (149% of control as determined morphometrically) appearing very early during carcinogenic treatment revealed almost normal activities of glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Hyperbasophilic crypts lacking mucus production were observed later and showed a loss of G6Pase, but marked increase of G6PDH and GAPDH activity. Mucus-rich signet ring cell carcinomas showed the same enzymatic pattern as the mucus-rich crypts, whereas mucus-free adenocarcinomas and undifferentiated carcinomas revealed a loss of G6Pase and highly increased G6PDH and GAPDH activities. The results showed that focal changes in polysaccharide content and in the activity of some enzymes of carbohydrate metabolism, as observed in various organs, also accompany the carcinogenic process in the colon. This supports the concept that aberrations in carbohydrate metabolism play an important role during the process of carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed1987

Comparison of the effects of antihypertensive drugs on pre- and postglomerular vessels of the hydronephrotic kidney.

The in vivo renal microvascular effects of three antihypertensive drugs: nitrendipine, a calcium entry blocker, and two direct-acting vasodilator agents, hydralazine and minoxidil, were compared. The dilator responses of pre- and postglomerular vessels were directly observed after the topical or intravenous administration of each drug using the hydronephrotic kidney preparation and television microscopy. When applied directly to the kidney to avoid changes in systemic blood pressure, all three drugs preferentially dilated the preglomerular vessels. The largest increases in preglomerular vessel diameters were observed with nitrendipine followed by hydralazine and minoxidil, in the order listed. These drugs produced little change in efferent arteriole diameters though acetylcholine evoked significant dilator responses of the same vessels. When infused intravenously to lower blood pressure, the predominant effect of the drugs was on the afferent arteriole. No significant changes in the efferent arteriole diameter were observed with any drug. These data demonstrate that these vasodilators, which act primarily at preglomerular sites, probably increase glomerular capillary pressure, but to differing degrees.

Administration, Topical↗
PubMed1987

Training perception of air flow obstruction in asthmatics.

Eighteen asthmatics, aged 7 to 43, rated their breathing on a scale of 0 to 5 (worst to best). They were then informed of their predicted normal peak expiratory flow rate (PEFR) and instructed in proper PEFR measurement. Each subject then estimated and measured PEFR under physician supervision and subsequently rated breathing, estimated and measured PEFR at home twice daily recording the observations. At the initial home observation, the correlation coefficient (r1) between estimated and measured PEFR was .98. After ten observations r1 was greater than or equal to .97 in all 18 subjects (group mean .99). The r1 remained unchanged in those subjects who completed 28 and 42 observations. The r1 was .98 when only the observations where measured PEFR was less than 20% predicted were considered, demonstrating the validity of the relationship during abnormal expiratory flow. Multiple regression analysis showed no significant trend in the difference between estimated and measured PEFR over time after the initial observation. Of 12 subjects, 4 were significant underestimators of PEFR and 3 were overestimators, but the magnitude of either tendency was relatively small. The correlation coefficient (r2) between a subjective verbal breathing score and measured PEFR ranged from -.23 to .92 on an individual basis over the three time periods, with statistically significant group mean values of .37, .39, and .45 at 10, 28, and 42 observations, respectively. The r2 for observations where measured PEFR was abnormal was only .14 and not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Characterization of a transporting system in rat hepatocytes. Studies with competitive and non-competitive inhibitors of phalloidin transport.

Primary cultures of rat hepatocytes were used for assaying several drugs not previously known for inhibiting the transport of phalloidin. In order to have 50% inhibition (IC50) of the entrance of a tritiated phallotoxin derivative ([3H]demethylphalloin, 1 microM) from the medium into the cells the following concentrations (microM) of the various inhibitors were determined: cyclolinopeptide (0.5), Nocloprost (5.0), Nileprost (7.0), beta-estradiol (42), Verapamil (70). For comparison, the corresponding IC50 values of some known antagonists of phalloidin toxicity were determined by the same method. Moreover, we studied several natural and synthetic phallotoxins and alpha-amanitin for their ability to displace [3H]demethylphalloin from the transporting system. Lineweaver-Burk plots made it obvious that two groups of inhibitors exist. Competitive inhibitors are, for example, antamanide, beta-estradiol, silybin, Nileprost, taurocholate, and the cyclic somatostatin analog cyclo[Phe-Thr-Lys-Trp-Phe-D-Pro], whereas Verapamil and monensin inhibit phallotoxin uptake in a non-competitive way. Considering the very different chemical features of the competitive inhibitors, we tentatively conclude that the phallotoxin transport system selects compounds not on the basis of their chemical features, but rather their physical properties. The physical properties of a typical substrate are low molecular mass, lipophilic nature, and, possibly the presence of rigid ring structures. Negative charges accelerate the transport of a substrate, while positive charges have the opposite effect. The phalloidin-transporting system may represent part of a hepatic equipment which clears portal blood from, for example, bile acids, lipophilic hormones, or xenobiotics. By chance, the transporting system incorporates phallotoxins into the hepatocytes leading to the death of these cells.

Amanitins↗
PubMed1986

[No indications for the mutagenicity of ofloxacin].

The antibacterial activity of ofloxacin, as demonstrated in the Rec assay, showed a harmful effect on the DNA of Bacteroides subtilis. In contrast, there was no significant harmful effect on the DNA of eukaryonts. Ofloxacin did not cause any point mutations, nor did it induce any in vivo or in vitro chromosome mutation in the systems tested. These tests lead us to the conclusion that there are no indications of ofloxacin having any mutagenic effects.

Animals↗