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Biomedical subjects

R Gasser

Publications and source records attributed to R Gasser.

At least 19 recordsLinked to original sources
PubMed2005

Increase in thyroid follicular cell tumors in nelfinavir-treated rats observed in a 2-year carcinogenicity study is consistent with a rat-specific mechanism of thyroid neoplasia.

The carcinogenic potential of nelfinavir mesylate (nelfinavir) was evaluated in a 2-year oral (gavage) study on Sprague-Dawley rats at dose levels of 0 (control), 0 (vehicle control), 100, 300 and 1000 mg/kg per day. At the end of the treatment, increased incidences of thyroid follicular cell hyperplasia and neoplasms were observed at 300 (males) and 1000 mg/kg per day (both sexes). There were no other treatment-related effects and no tumors at other sites. Results from previous studies indicated a number of effects in the liver and thyroid, as well as metabolic profiles that suggested nelfinavir might cause thyroid hyperplasia/neoplasia secondary to hormone imbalance by altering thyroid hormone disposition. To investigate this hypothesis, the effects of nelfinavir on gene expression in rat hepatocytes and liver slices (in vitro), thyroxine plasma clearance, and thyroid gland function were evaluated. Compared to controls, gene expression analyses demonstrated an increased expression of glucuronyltransferase (UDPGT) and CYP450 3A1 in nelfinavir-treated rat hepatocytes and liver slices. In rats treated with nelfinavir (1000 mg/kg per day) for 4 weeks, liver weights and centrilobular hepatocellular hypertrophy were increased and minimal to mild diffuse thyroid follicular cell hypertrophy and follicular cell hyperplasia were evident in the thyroid gland. Thyroid-stimulating hormone (TSH) levels were significantly increased (three-fold), while tri-iodothyronine (T3)/tetra-iodothyronine (T4) and reverse T3(rT3) levels were unchanged, indicating that a compensated state to maintain homeostasis of T3/T4 had been achieved. Plasma 125I-thyroxine clearance was increased and the plasma thyroxine AUC0-48 was decreased (24%) compared to control. In conclusion, these data indicate that thyroid neoplasms observed in the nelfinavir-treated rats were secondary to thyroid hormone imbalance. Increased thyroxine clearance contributes to the effects of nelfinavir on thyroid gland function and is probably a result of UDPGT induction that leads to elevated TSH levels in the rat and eventual thyroid neoplasia. These results are consistent with a well-recognized rat-specific mechanism for thyroid neoplasms.

Adenocarcinoma, Follicular↗
PubMed2003

Proteomic analysis of the cell envelope fraction of Escherichia coli.

We applied proteomics technologies to analyze a membrane preparation of Escherichia coli, wild type strain and of transformants expressing human cytochrome P450s. The proteins were analyzed by two-dimensional electrophoresis and identified by matrix-assisted laser desorption ionization mass spectrometry. The membrane proteins were solubilized with both mild detergents such as CHAPS and strong detergents, such as sodium and lithium dodecyl sulfate, sodium cholate and sodium deoxycholate. In the E. colimembrane fraction, 394 different gene products were identified. Approximately 28% of them were predicted to be integral membrane proteins, of which 100 proteins have been predicted to carry one transmembrane region, ten proteins to carry two, and two proteins to include three transmembrane domains. The remaining are probably membrane-associated and cytosolic proteins. Cytochrome P450s did not enter the immobilized pH gradient strips but were efficiently analyzed in a two-dimensional, two-detergent system. Use of strong solubilizing agents resulted in the detection of about 20 membrane proteins, which were not detected following extraction with mild detergents and chaotropes. The present database is one of the largest for membrane proteins.

Electrophoresis, Gel, Two-Dimensional↗
PubMed2002

[Is there new knowledge on embryology and functional anatomy of human mimetic muscles and the upper lip? A contribution to point selection, skin incision and muscle reconstruction in primary lip-nose reconstruction of uni- and bilateral lip-jaw-palatal clefts].

BACKGROUND: The great variety of primary cheiloplastic procedures in CLP patients shows that there is disagreement regarding the embryological development of this part of the face, the point selection, skin incision philosophy, and the macroscopic and microscopic functional anatomy of the human muscles of facial expression. We suppose from findings in Asian and African populations that the real embryological development of the upper lip differs from current textbook descriptions. Our own anatomical and embryological investigations serve as a basis for a critical discussion of different techniques of muscle reconstruction, point selection, and skin incision and for a description of an embryologically, functionally, and anatomically oriented operation technique for different entities of CLP. METHODS: The findings of this study result from investigations of the embryonal and early fetal development from the 26th to the 112th i.u. day in REM pictures of the Anatomical Institute of the University of Göttingen (n = 8) and serial histological investigations of the Carnegie and Hooker-Humphrey Collections at the Armed Forces Institute of Pathology, Washington, D.C. (n = 40). Furthermore, we carried out microsurgical dissections of the muscles of facial expression, the osseous and cartilaginous parts of the nose, and the midfacial sutures in two adult heads without congenital disorders and one newborn head with a primary unilateral complete cleft of the lip and alveolus. RESULTS AND DISCUSSION: The formation of the lower third of the upper lip is the result of contact of the maxillary bulges in the midline below the prolabium. According to this finding, the point selections and skin incisions have to be modified in the midline region in different types of uni- and bilateral CLP. Our technique of primary dissection, reorientation, and suturing of the muscles of facial expression is presented. The muscle reconstruction has to be performed independently from the skin preparation.

Cleft Lip↗
PubMed2002

Cardiac failure and multiple organ dysfunction syndrome in a patient with endocrine adenomatosis.

In this case report, we present the successful therapy of severe cardiac failure in pituitary adrenal insufficiency. A previously healthy 56-year-old-man in pituitary coma due to an atypical variant of multiple endocrine adenomatosis (pituitary adenoma and pheochromocytoma) suffered from cardiac failure resistant to catecholamine and standard hydrocortisone therapy. After two bolus injections of dexamethasone (2 x 24 mg) mean arterial pressure and cardiac function dramatically improved, probably due to restoration of permissive effects on catecholamine action and reversal of pathophysiological mechanisms of cardiac failure. We conclude that in patients with severe cardiovascular failure in pituitary coma the administration of potent glucocorticoids may be more effective in reversing cardiovascular failure than standard dosages of hydrocortisone.

Adenoma↗
PubMed2002

G-455A polymorphism of the fibrinogen beta gene and deep vein thrombosis.

BACKGROUND: Elevated fibrinogen levels have been linked to increased risk for deep venous thrombosis, although it is not clear whether fibrinogen is causal or rather a marker for the presence of other risk factors. A common G/A polymorphism in the gene for the fibrinogen beta-chain (FGB G-455A) is associated with elevated fibrinogen levels. The present study was designed to analyze the role of this genetic marker for deep venous thrombosis. MATERIALS AND METHODS: We performed a case-control study including 307 patients with documented deep venous thrombosis and 316 control subjects. beta-fibrinogen genotypes were determined by allele-specific polymerase chain reaction. RESULTS: GG, GA and AA genotype frequencies were similar among the patients (53.1%, 41.0, 5.9) and controls (51.6%, 42.1, 6.3; P = 0.92). Fibrinogen levels of the patients (median 3.72 g l-1; range 1.93-11.6) did not differ significantly from those of the controls (3.76; 2.17-9.99). Carriers of the homozygous AA genotype had significantly higher fibrinogen levels than noncarriers (patients: 5.32 vs. 3.59; P = 0.024; controls: 6.29 vs. 3.72; P = 0.048). CONCLUSION: Our data suggest that the fibrinogen-elevating FGB G-455A gene polymorphism is not linked to an increased risk for deep venous thrombosis.

Alleles↗
PubMed2001

Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate.

Troglitazone is a thiazolidinedione insulin sensitizer drug for the treatment of type 2 non-insulin-dependent diabetes mellitus (NIDDM). Based on an increasing number of reports on troglitazone-associated liver toxicity, the cholestatic potential of troglitazone and its major metabolite troglitazone sulfate has been investigated. In isolated perfused rat livers troglitazone (10 microM) reduced the bile flow by 25% (female) to 50% (male) within 60 min. After single intravenous administrations of troglitazone to rats of both genders, rapid and dose-dependent increases in the plasma bile acid concentrations were observed, with male rats being more sensitive than female rats. In male rat liver tissue fivefold higher troglitazone sulfate levels were measured as compared to female rat liver tissue. This difference was due to the formation rate of troglitazone sulfate, which was four times faster in cytosolic fractions of male rat liver as compared to female rat liver (Clint=132 and 35 microl min(-1) mg(-1), respectively). Troglitazone sulfate strongly inhibited the ATP-dependent taurocholate transport mediated by the canalicular bile salt export pump (Bsep) in isolated canalicular rat liver plasma membrane preparations of both genders (IC(50) value of 0.4-0.6 microM), while troglitazone was 10 times less potent (IC(50) values of 3.9 microM). This high Bsep inhibition potential and the efficient formation and accumulation of troglitazone sulfate in liver tissue, suggested that troglitazone sulfate was mainly responsible for the interaction with the hepatobiliary export of bile acids at the level of the canalicular Bsep in rats. Such an interaction might lead potentially also in man to a troglitazone-induced intrahepatic cholestasis, potentially contributing to the formation of troglitazone-induced liver injuries.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Mutation scanning for sequence variation in three mitochondrial DNA regions for members of the Contracaecum osculatum (Nematoda: Ascaridoidea) complex.

Anisakid nematodes of seals from different geographical origins, previously identified by multilocus enzyme electrophoresis as Contracaecum osculatum A (CoA), C. osculatum B (CoB), C. osculatum C (CoC), C. osculatum D (CoD), C. osculatum E (CoE) and C. osculatum baicalensis (Cob), were characterised genetically using a mutation scanning approach, in order to define genetic markers for their specific identification and differentiation. Three mitochondrial DNA (mtDNA) regions, namely cytochrome c oxidase subunit I (COI), and the small and large subunits of rRNA (ssrRNA and IsrRNA, respectively) were amplified separately from individual nematodes by polymerase chain reaction (PCR), analysed by single-strand conformation polymorphism (SSCP), and samples displaying sequence variability were subjected to sequencing. Forty-six haplotypes were defined for 62-66 individuals (representing the six members of C. osculatum). All taxa except CoD and CoE could be identified, or delineated from one another, by nucleotide differences in the COI, ssrRNA and/or IsrRNA sequences. For all three mtDNA regions, 4 (10.5%), 7 (18.4%), 15 (39.5%) and 11 (28.9%) of 38 nucleotide positions were considered diagnostic (fixed) and could thus unequivocally delineate CoA, CoB, CoC and Cob. The lack of an unequivocal nucleotide difference in any of the three mtDNA sequences between CoD and CoE was in accordance with previous ribosomal DNA sequence data but inconsistent with multilocus enzyme electrophoretic data. Using all fixed nucleotide positions, CoA, CoD/E and CoB were genetically more similar to Cob than each was to CoC, similar to previous findings. In spite of not being able to distinguish among all six taxa of C. osculatum, the present study demonstrated clearly the usefulness and attributes of the mutation scanning approach for investigating population genetic structures of species of parasitic nematodes.

Animals↗
PubMed2001

Molecular and phylogenetic characterisation of Cryptosporidium from birds.

Avian isolates of Cryptosporidium species from different geographic locations were sequenced at two loci, the 18S rRNA gene and the heat shock gene (HSP-70). Phylogenetic analysis of the sequence data provided support for the existence of a new avian species of Cryptosporidium infecting finches and a second species infecting a black duck. The identity of Cryptosporidium baileyi and Cryptosporidium meleagridis as valid species was confirmed. Also, C. baileyi was identified in a number of isolates from the brown quail extending the host range of this species.

Animals↗
PubMed2000

In vitro metabolism of acitretin by human liver microsomes: evidence of an acitretinoyl-coenzyme A thioester conjugate in the transesterification to etretinate.

The aromatic retinoid acitretin is the primary active metabolite of etretinate, and in this study we investigated the ethyl esterification of acitretin to etretinate using [(14)C]acitretin and human liver microsomes. Samples were analysed by TLC, HPLC, and LC-MS. Essential requirements for the transesterification reaction were identified and included viable microsomal protein, ATP, CoASH, and ethanol. Human liver microsomes catalysed formation of acitretinoyl-CoA at the rate of 0.08 +/- 0.02 nmol/min/mg (mean +/- SD, N = 10). Acitretinoyl-CoA was pivotal for the transesterification to etretinate and in the presence of methanol, ethanol, n-propanol, n-butanol, and hexanol, the corresponding esters, namely methyl-, ethyl (etretinate)-, propyl-, butyl-, and hexyl-acitretinate, were formed. On average, 1.7% of the acitretin present in the incubation was converted to etretinate in the presence of ethanol. In the absence of ethanol, transesterification did not proceed. Inhibition of the ester hydrolysis of etretinate by bis-p-nitrophenylphosphate (BNPP, 1 mM) prevented futile cycling of etretinate via acitretinoyl-CoA. An additional finding was that acitretin (15-30 microM) activated significantly human liver microsomal long-chain fatty acid-CoA ligase (E.C.6.2.1.3, LCL), resulting in enhanced formation of palmitoyl-CoA. This study demonstrated that in the presence of ethanol the ethyl esterification of acitretin to etretinate proceeds via formation of acitretinoyl-CoA. Predicting clearance of acitretin in vivo via this unique metabolic pathway will be a challenge, as the intracellular concentration of ethanol could never be predicted with any degree of accuracy in humans.

Acetaldehyde↗
PubMed2000

Segmental degradation of left ventricular wall motion after persistent coronary fistula in a posttransplantation patient: a case report and short review of literature.

A 50-year-old man received an orthotopic heart transplant because of severe coronary heart disease and congestive heart failure. Two years after the transplantation, a continuous murmur occurred at the left sternal edge after repeated endomyocardial biopsies. Echocardiography and coronary angiography revealed a dilated left anterior descending artery with a fistula to the right ventricle. The circumflex was large with an equally postero-lateral branch, and the right coronary artery was rather small with collaterals to the distal part of the left anterior descending branch. The patient had refused any intervention to close the fistula. The left ventricular levogram was normal. Two years later, in a follow-up angiogram, the left ventricular ejection fraction had decreased as a result of hypo- and akinesis of the apex and posterior wall. We suggest that this local wall motion disturbance derives from a steal phenomenon rather than being a sequela of rejection. The decrease in left ventricular ejection fraction was associated with shortness of breath upon moderate exercise. Standard heart failure medication relieved the patient's symptoms. The observation of local wall motion disturbances in this case, as well as conflicting views in the literature, raises the question whether postbiopsy coronary fistulas in transplant patients should be closed.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Partial laparoscopic adrenalectomy for aldosterone-producing adenoma: short-and long-term results.

BACKGROUND AND PURPOSE: Laparoscopic surgery for adrenal gland tumors is the gold standard operative approach now. Adrenal-sparing surgery has special indications. We demonstrated the safety and feasibility of performing adrenal-sparing surgery by means of laparoscopy for aldosterone-producing adenoma (Conn's syndrome). PATIENTS AND METHODS: Between 1995 and 1999, seven patients with Conn's syndrome had laparoscopic adrenal-sparing resection of their tumors. These patients were followed up by means of radiology and biochemistry. RESULTS: All seven patients had successful laparoscopic surgery without complications. Most patients were discharged in 2 to 6 days (mean 3 days). At follow-up, the six patients investigated had normal blood pressure. No recurrences have been encountered with a median follow-up of 12 months in these six patients. CONCLUSIONS: Adrenal-sparing resection of tumors causing primary hyperaldosteronism is technically feasible by means of laparoscopy. This procedure has the advantage of keeping a greater reserve of normal adrenal tissue and of rapid postoperative recovery.

Adenoma↗
PubMed2000

Change in left atrial and ventricular dimensions during and immediately after exercise.

PURPOSE: The aim of this study was to evaluate differences in the left atrial (LAD), total ventricular end-diastolic (TEDD), end-systolic diameters (TESD), and left ventricular shortening fraction (SF) compared with heart rate (HR) and systolic blood pressure (SBP) during exercise and recovery. METHODS: Healthy young male (N = 15) and female (N = 16) subjects performed an incremental cycle ergometer test in upright position, and three phases of energy supply were defined by means of blood lactate concentration (LA) and respiratory gas exchange variables (I: aerobic; II: aerobic-anaerobic transition; III: anaerobic). Subjects were required to rest their arms on a steering bar and to lean their upper body forward; two dimensional (2-D) echocardiograms were obtained over the left parasternal area at rest (R), at the end of each phase, immediately within 15 s post, and 6 min after exercise (6 min). By using VINGMED's "Anatomical M-Mode," it was possible to extract M-Mode Sweeps from stored 2-D-Loops and perform the M-Mode measurement. RESULTS: In contrast to the significant decrease in TEDD and TESD from III to 15 s up to resting values and the significant increase in SF from III to 15 s, the moderate decrease in HR immediately post exercise (15 s) was not significant. The SBP showed a significantly decrease from III to 15 s; in contrast to TEDD, TESD, and SF, the values at 15 s were comparable with the values at II. For LAD, significant increase during exercise and a decrease during recovery were observed. Sex-specific differences of changes in measured variables could not be found. CONCLUSION: We concluded that post exercise measurement of left ventricular and atrial dimensions or SF were not valid to describe heart function at maximal exercise although immediately post exercise HR was near maximal level.

Adult↗
PubMed2000

Lack of interaction between tolcapone and tolbutamide in healthy volunteers.

To assess the effect of tolcapone (an inhibitor of cytochrome P450 [CYP] 2C9 in vitro) on the pharmacokinetics and hypoglycemic effect of the CYP 2C9 substrate tolbutamide, 12 healthy male volunteers were randomized to receive a single dose of tolbutamide 500 mg plus either placebo or tolcapone 200 mg after an overnight fast and 30 minutes after the start of a 6.5-hour 5% glucose infusion (150 mL/h). The participants crossed over to receive the alternative regimen after a washout period of at least 7 days. Tolcapone had no effect on the pharmacokinetics of tolbutamide or its metabolites and did not influence the effect of tolbutamide on plasma glucose concentrations. No serious adverse events or abnormal laboratory results or vital signs were reported. In conclusion, clinically relevant drug-drug interactions between tolcapone and tolbutamide when given together in clinical practice appear unlikely.

Administration, Oral↗
PubMed2000

[Free intracellular magnesium in myocardium--measurement and physiological role--state of the art].

Magnesium is an important intracellular cation which is known to participate in over 300 biochemical reactions of the cell. Most of the cell's Mg2+ is bound to intracellular structures, and only 5% of the total Mg2+ are unbound and thus biologically active. Clinical data concerning the therapeutic value of Mg2+ in various conditions like myocardial infarction are conflicting, experimental support for a specific therapy is still lacking, because values of free intracellular myocardial Mg2+ as well as behaviour of (Mg2+)i during ischemia or changes of extracellular ion-concentrations have not been elucidated as yet. Various techniques like Mg2+ sensitive dyes, nuclear magnetic resonance spectroscopy or Mg2+ selective microelectrodes have been employed, each of these techniques, however, harbours serious limitations.

Coloring Agents↗