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Biomedical subjects

C Meier

Publications and source records attributed to C Meier.

At least 73 records · Page 4Linked to original sources
PubMed2000

Inhibitory effect of cycloSaligenyl-nucleoside monophosphates (cycloSal-NMP) of acyclic nucleoside analogues on HSV-1 and EBV.

The in vitro antiviral activity of a new series of cycloSal-pro-nucleotides derived from the acyclic nucleoside analogues aciclovir and penciclovir against herpes simplex virus type 1 (HSV-1), thymidine kinase deficient (TK-) HSV-1, and Epstein-Barr virus (EBV) was evaluated. Using the XTT-based tetrazolium reduction assay EZ4U, the cycloSal derivatives were examined for their antiviral and cytotoxic effects in HSV-1 as well as HSV-1-TK--infected Vero cells. The anti-EBV activity was assessed by means of an EBV DNA hybridization assay using a digoxigenin-labeled probe specific for the Bam H1-W-fragment of the EBV genome and by measuring viral capsid antigen (VCA) expression in P3HR-1 cells by indirect immunofluorescence. Among the new cycloSal-phosphotriesters the three aciclovir monophosphates proved to be potent and selective inhibitors of HSV-1 replication, EBV DNA synthesis and EB-VCA expression. Of interest is the retention of activity of the aciclovir monophosphates in HSV-1-TK--infected cells. Particularly 3-methyl-cycloSal-aciclovir monophosphate retained the same effectiveness, as compared to the wild type virus strain. In contrast to the aciclovir pro-nucleotides the penciclovir cycloSal-phosphotriesters exhibited at best only a marginal antiviral effect on HSV and EBV replication.

Acyclovir↗
PubMed2000

[Ogilvie syndrome with cecal perforation. A rare complication after isolated thoracic trauma. Case report and current literature review].

In reviewing 750 cases of acute colonic pseudo-obstruction from the literature, the most commonly associated disorders are listed and the therapeutical management is critically discussed. The authors describe an additional case of a 77-year-old male with ogilvie's syndrome following isolated thoracic trauma. Ogilvie's syndrome has been used synonymously with acute colonic pseudo-obstruction (ACPO) of the colon, first defined by Sir Heneage Ogilvie in 1948. If inappropriately managed, the massive colonic dilatation may lead to caecal ischaemia and perforation with a high mortality rate. Aetiology and pathogenesis of the syndrome are still unknown, but mostly ACPO is associated with a wide variety of medical conditions. Often it appears to be a complication after abdominal or pelvic surgery or trauma. In few cases the pseudo-obstruction is isolated and therefore truly idiopathic. Conservative treatment is indicated if the caecum is less than 12 cm in diameter. If there is a progressive increase in diameter or no improvement is seen, the colon should be decompressed without further delay. The indications for surgery are failure of conservative treatment and colonoscopy, signs for ceacal ischaemia or perforation. The choice of procedure, coecostomy or resection, is dictated by the state of the caecum. Due to a high mortality rate (up to 50%) if the caecum is perforated, an aggressive therapeutical management should be applied.

Aged↗
PubMed2000

Fusion genetic analysis of gibberellin signaling mutants.

A fusion genetic strategy was used to identify gibberellin (GA) signaling mutants in transgenic Arabidopsis expressing the beta-glucuronidase (GUS) and firefly luciferase (LUC) reporter genes under control of the GA-responsive GASA1 promoter. Initial analyses determined the spatial and temporal patterns of reporter expression, and showed that reporter induction by GA was antagonized by ABA. gamma-Irradiated M2 progeny with altered reporter activities were identified by LUC bioimaging followed by GUS assays and northern hybridization of the endogenous GASA1 mRNA. Genetic analysis showed that three mutants, which overexpressed both reporters and endogenous GASA1, were caused by recessive (goe1 and goe2, for GASA over-expressed) and semi-dominant (goe3) mutations at different loci. These mutants are altered in their sensitivity to GA and the GA biosynthetic inhibitor paclobutrazol, and in the expression of several GA signaling related genes.

Base Sequence↗
PubMed2000

Cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate: efficient intracellular delivery of d4TMP.

Cyclosaligenyl-2',3'-didehydro-2', 3'-dideoxythymidine-5'-monophosphate (cycloSal-d4TMP) is a potent and selective inhibitor of human immunodeficiency virus replication in cell culture and differs from other nucleotide prodrug approaches in that it is designed to selectively deliver the nucleotide 5'-monophosphate by a controlled, chemically induced hydrolysis. Its antiviral efficacy in cell culture is at least as good as, if not superior to, that of d4T. CycloSal-d4TMP was found to lead to the efficient intracellular release of d4TMP in a variety of cell lines, including both wild-type CEM and thymidine kinase-deficient CEM/TK(-) cells. Under similar experimental conditions, exposure of CEM/TK(-) cells to d4T failed to result in significant d4TTP levels. The intracellular conversion of cycloSal-d4TMP proved to be both time and dose dependent. The half-life of d4TTP generated intracellularly from d4T- or cycloSal-d4TMP-treated CEM cells was approximately 3.5 h, and the intracellular ratios of d4TTP/d4TMP in cells exposed to cycloSal-d4TMP gradually increased from 1 to 3.4 upon prolonged incubation. Radiolabeled cycloSal-d4TMP could be separated as its two R(p) and S(p) diastereomers on high-performance liquid chromatography. The R(p) diastereomer of cycloSal-d4TMP was 3- to 7-fold more efficient in releasing d4TMP and generating d4TTP than the S(p) cycloSal-d4TMP diastereomer. This correlated well with the 5-fold more pronounced antiviral activity of the R(p) diastereomer versus the S(p) diastereomer. d4TMP is a poor substrate for the cytosolic 5'(3')-deoxyribonucleotidase (V(max)/K(m) for d4TMP: 0.08 of V(max)/K(m) for dTMP) and is only slowly hydrolyzed to d4T. This contributes to the efficient conversion of the prodrug of d4TTP.

5'-Nucleotidase↗
PubMed2000

Hypervolumetric hemodilution with HES 100/0.5 10% in patients with peripheral arterial occlusive disease (Fontaine, stage II): an open clinical and pharmacological phase IV study.

The efficacy of three weekly interventions with hypervolumetric hemodilution of a new preparation of hydroxyethyl starch (HES 100/0.5, 10%, C2/C6 substitution ratio of 6.5) on pain-free walking distance of patients with peripheral arterial occlusive disease (PAOD) stage IIb on the Fontaine classification was investigated. In addition quantitative data on the pharmacokinetic properties of this HES preparation, and it's impact on hemorheology, hemostasis and homeostasis were shown. Ten patients were included according to a predefined protocol, and treated openly with 500 ml HES 100/0.5 10% on nine occasions over 18 days. Pain-free walking distance, the main outcome measure, showed a mean increase of 82 m (+60%). Hematocrit decreased 4 percentage points on average (5.5 percentage points one hour after interventions). Plasma viscosity dropped 5% on average with significant changes immediately after interventions only in patients whose baseline values had been equal to or above the 2 s reference area. Erythrocyte aggregation decreased by 16% in the course of treatment (8% immediately after interventions), systolic blood pressure by 13%, and total protein by 7%. Complement showed a trend towards lower values (-20%), and creatinine, pH and urine viscosity remained unchanged. Apart from complement changes, all reductions mirrored the dilution effects. As to pharmacokinetics, serum mean molecular weight distribution was very similar to that of the infusion. A minor adverse drug reaction (light, spontaneously disappearing pruritus) was observed in one case.

Aged↗
PubMed2000

Finding similar cases within a hospital information system.

Most of the theoretical medical knowledge comes from literature. The knowledge obtained from the vast majority of patients is then lost. The vast majority of patients do not participate in the elaboration of medical knowledge, apart from the lucky few entering a clinical trial or a published case study. Moreover, locally treated patients do not always correspond to the same time, space or age context as literature patients. How can the knowledge of one patient be used for treating other patients? How can we save the knowledge of our own patients? Hospital information systems contain a lot of detailed and precise information about many patients over several years. Databases containing detailed information can provide solutions based on case analysis (Case-based reasoning or "similar case approach"). An example of a Geneva's decision system called Archimed is shown here.

Artificial Intelligence↗
PubMed1999

LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine.

Glycoprotein-associated amino acid transporters (gpaAT) are permease-related proteins that require heterodimerization to express their function. So far, four vertebrate gpaATs have been shown to associate with 4F2hc/CD98 for functional expression, whereas one gpaAT specifically associates with rBAT. In this study, we characterized a novel gpaAT, LAT2, for which mouse and human cDNAs were identified by expressed sequence tag data base searches. The encoded ortholog proteins are 531 and 535 amino acids long and 92% identical. They share 52 and 48% residues with the gpaATs LAT1 and y(+)LAT1, respectively. When mouse LAT2 and human 4F2hc cRNAs were co-injected into Xenopus oocytes, disulfide-linked heterodimers were formed, and an L-type amino acid uptake was induced, which differed slightly from that produced by LAT1-4F2hc: the apparent affinity for L-phenylalanine was higher, and L-alanine was transported at physiological concentrations. In the presence of an external amino acid substrate, LAT2-4F2hc also mediated amino acid efflux. LAT2 mRNA is expressed mainly in kidney and intestine, whereas LAT1 mRNA is expressed widely. Immunofluorescence experiments showed colocalization of 4F2hc and LAT2 at the basolateral membrane of kidney proximal tubules and small intestine epithelia. In conclusion, LAT2 forms with LAT1 a subfamily of L-type gpaATs. We propose that LAT1 is involved in cellular amino acid uptake, whereas LAT2 plays a role in epithelial amino acid (re)absorption.

Amino Acid Transport Systems↗
PubMed1999

The anaerobic ribonucleotide reductase from Escherichia coli. The small protein is an activating enzyme containing a [4fe-4s](2+) center.

For deoxyribonucleotide synthesis during anaerobic growth, Escherichia coli cells depend on an oxygen-sensitive class III ribonucleotide reductase. The enzyme system consists of two proteins: protein alpha, on which ribonucleotides bind and are reduced, and protein beta, of which the function is to introduce a catalytically essential glycyl radical on protein alpha. Protein beta can assemble one [4Fe-4S] center per polypeptide enjoying both the [4Fe-4S](2+) and [4Fe-4S](1+) redox state, as shown by iron and sulfide analysis, Mössbauer spectroscopy (delta = 0.43 mm.s(-1), DeltaE(Q) = 1.0 mm.s(-1), [4Fe-4S](2+)), and EPR spectroscopy (g = 2. 03 and 1.93, [4Fe-4S](1+)). This iron center is sensitive to oxygen and can decompose into stable [2Fe-2S](2+) centers during exposure to air. This degraded form is nevertheless active, albeit to a lesser extent because of the conversion of the cluster into [4Fe-4S] forms during the strongly reductive conditions of the assay. Furthermore, protein beta has the potential to activate several molecules of protein alpha, suggesting that protein beta is an activating enzyme rather than a component of an alpha(2)beta(2) complex as previously claimed.

Anaerobiosis↗
PubMed1999

Developing Schwann cells acquire the ability to survive without axons by establishing an autocrine circuit involving insulin-like growth factor, neurotrophin-3, and platelet-derived growth factor-BB.

Although Schwann cell precursors from early embryonic nerves die in the absence of axonal signals, Schwann cells in older nerves can survive in the absence of axons in the distal stump of transected nerves. This is crucially important, because successful axonal regrowth in a damaged nerve depends on interactions with living Schwann cells in the denervated distal stump. Here we show that Schwann cells acquire the ability to survive without axons by establishing an autocrine survival loop. This mechanism is absent in precursors. We show that insulin-like growth factor, neurotrophin-3, and platelet-derived growth factor-BB are important components of this autocrine survival signal. The secretion of these factors by Schwann cells has significant implications for cellular communication in developing nerves, in view of their known ability to regulate survival and differentiation of other cells including neurons.

Animals↗
PubMed1999

cycloSal-Pronucleotides of 2',3'-dideoxyadenosine and 2', 3'-dideoxy-2',3'-didehydroadenosine: synthesis and antiviral evaluation of a highly efficient nucleotide delivery system.

The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-ddAMP (9a-d) and cycloSal-d4AMP (10a-d) derivatives of the antiviral purine dideoxynucleoside analogues 2', 3'-dideoxyadenosine (ddA) (2) and 2',3'-dideoxy-2', 3'-didehydroadenosine (d4A) (3) are reported. These potential pronucleotides release ddAMP (7) or d4AMP (8) selectively by a controlled, chemically induced tandem reaction. All new compounds 9 and 10a-d were synthesized in good yields using our previously reported phosphorus(III) method starting from substituted salicyl alcohols 14a-h. The phosphotriesters 9 and 10 were obtained with a stereochemical preference of 2:1 with respect to the configuration at the phosphorus center. In an 1-octanol/water mixture phosphotriesters 9 and 10 exhibited 7-43-fold higher lipophilicity than the parent nucleosides ddA (2) and d4A (3) as judged by their log P values. In hydrolysis studies, 9 and 10 decomposed under mild aqueous basic conditions releasing solely ddAMP (7) and d4AMP (8), as well as the diols 14. Further hydrolysis studies under acidic conditions showed a marked increase in stability with respect to the acid-catalyzed cleavage of the glycosyl bond. Phosphotriesters 9 and 10 exhibited antiviral potencies against wild-type HIV-1 and HIV-2 strains in human T-lymphocyte (CEM/O) cells that were, respectively, 100- and 600-fold higher than those of ddA (2) and d4A (3). Furthermore, all triesters 9 and 10 were markedly more active than the corresponding ddI compounds 11 and 12, which supports the concept of the delivery of the adenine nucleotides. Studies with adenosine deaminase (ADA) and adenosine monophosphate deaminase (AMPDA) showed that the triesters were not substrates for enzymatic deamination. The studies reported herein demonstrate conclusively that the cycloSal triesters deliver exclusively the nucleotides ddAMP and d4AMP, not only under chemical-simulated hydrolysis but also under intracellular conditions fulfilling the adenosine deaminase bypass premise.

3T3 Cells↗
PubMed1999

cycloSal-Pronucleotides of 2'-fluoro-ara- and 2'-fluoro-ribo-2',3'- dideoxyadenosine as a strategy to bypass a metabolic blockade.

Novel, lipophilic cycloSal triesters 4a-c and 5a-c were synthesized, respectively, from the ara- and ribo-configurated 2'-fluorinated-2', 3'-dideoxyadenosines 2 and 3. The cycloSal phosphotriesters were used as tools to study the effects of the two different sugar pucker conformations induced by two opposite configurations of the fluorine substituent at C2' of the dideoxyribose moiety. F-ara-ddA (2) is known to be an active anti-HIV agent, whereas the ribo-analogue 3 is inactive. Hydrolysis studies with the triester precursors 4a-c and 5a-c showed selective formation of the monophosphates of 2 and 3. The lipophilicity of the triester prodrugs was considerably increased by the cycloSal mask with respect to ddA (1), F-ara-ddA (2), and F-ribo-ddA (3). Phosphotriesters 4 and 5 proved to be completely resistant to ADA and AMPDA deamination. In parallel experiments, ribo-nucleoside 3 showed a 50-fold faster deamination rate relative to the ara-analogue 2. Against HIV in CEM cells, the phosphotriesters 4 proved to be 10-fold more potent than the parent nucleoside 2. Furthermore, the prodrugs 4 were active against MSV-induced transformation of C3H/3T3 fibroblasts, while 2 was inactive. More interestingly, the ribo-configurated phosphotriesters 5, prepared from the inactive F-ribo-ddA (3), showed a level of anti-HIV activity that was even higher than that of F-ara-ddA (2). Our findings clearly prove that the application of the cycloSal-pronucleotide concept to F-ribo-ddA (3) overcomes a metabolic blockade in the formation of the corresponding monophosphate.

3T3 Cells↗
PubMed1999

Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family.

Amino acid transport across cellular membranes is mediated by multiple transporters with overlapping specificities. We recently have identified the vertebrate proteins which mediate Na+-independent exchange of large neutral amino acids corresponding to transport system L. This transporter consists of a novel amino acid permease-related protein (LAT1 or AmAT-L-lc) which for surface expression and function requires formation of disulfide-linked heterodimers with the glycosylated heavy chain of the h4F2/CD98 surface antigen. We show that h4F2hc also associates with other mammalian light chains, e.g. y+LAT1 from mouse and human which are approximately 48% identical with LAT1 and thus belong to the same family of glycoprotein-associated amino acid transporters. The novel heterodimers form exchangers which mediate the cellular efflux of cationic amino acids and the Na+-dependent uptake of large neutral amino acids. These transport characteristics and kinetic and pharmacological fingerprints identify them as y+L-type transport systems. The mRNA encoding my+LAT1 is detectable in most adult tissues and expressed at high levels in kidney cortex and intestine. This suggests that the y+LAT1-4F2hc heterodimer, besides participating in amino acid uptake/secretion in many cell types, is the basolateral amino acid exchanger involved in transepithelial reabsorption of cationic amino acids; hence, its defect might be the cause of the human genetic disease lysinuric protein intolerance.

Amino Acid Sequence↗
PubMed1999

'Friendship' for fitness in chimpanzees?

It has been repeatedly suggested that primates trade social services for fitness benefits in their relationships with the opposite sex. We tested this proposal in a colony of captive chimpanzees, Pan troglodytes, by examining behavioural data on grooming, agonistic support and food sharing in relation to genetically established paternity. We found no support for the notion of trade. First, males did not sire more offspring with females that they actively groomed more frequently, that they supported more often or with which they shared food more frequently. Correspondingly, females did not give birth to more offspring sired by males from which they received more services. Second, males that showed more affiliative behaviour towards females in general did not sire more progeny. Furthermore, females did not bear more offspring sired by males to which they themselves directed more sociopositive behaviour. Results from this captive colony are compatible with those reported for chimpanzees under natural conditions. Copyright 1999 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed1999

Iron coordination geometry in full-length, truncated, and dehydrated forms of human tyrosine hydroxylase studied by Mössbauer and X-ray absorption spectroscopy.

Full-length human tyrosine hydroxylase 1 (hTH1) and a truncated enzyme lacking the 150 N-terminal amino acids were expressed in Escherichia coli and purified either with or without (6 x histidine) N-terminal tags. After reconstitution with 57Fe(II), the Mössbauer and X-ray absorption spectra of the enzymes were compared before and after dehydration by lyophilization. Before dehydration, > 90% of the iron in hTH1 had Mössbauer parameters typical for high-spin Fe(II) in a six-coordinate environment [isomer shift delta (1.8-77 K) = 1.26-1.24 mm s-1 and quadrupole splitting delta EQ = 2.68 mm s-1]. After dehydration, the Mössbauer spectrum changed and 63% of the area could be attributed to five-coordinate high-spin Fe(II) (delta = 1.07 mm s-1 and delta EQ = 2.89 mm s-1 at 77 K), whereas 28% of the iron remained as six-coordinate high-spin Fe(II) (delta = 1.24 mm s-1 and delta EQ = 2.87 mm s-1 at 77 K). Similar changes upon dehydration were observed for truncated TH either with or without the histidine tag. After rehydration of hTH1 the spectroscopic changes were completely reversed. The X-ray absorption spectra of hTH1 in solution and in lyophilized form, and for the truncated protein in solution, corroborate the findings derived from the Mössbauer spectra. The pre-edge peak intensity of the protein in solution indicates six-coordination of the iron, while that of the dehydrated protein is typical for a five-coordinate iron center. Thus, the active-site iron can exist in different coordination states, which can be interconverted depending on the hydration state of the protein, indicating the presence or absence of a water molecule as a coordinating ligand to the iron. The present study explains the difference in iron coordination determined by X-ray crystallography, which has shown a five-coordinate iron center in rat TH, and by our recent spectroscopic study of human TH in solution, which showed a six-coordinated iron center.

Absorptiometry, Photon↗
PubMed1999

Iron-sulfur interconversions in the anaerobic ribonucleotide reductase from Escherichia coli.

The anaerobic ribonucleotide reductase from Escherichia coli contains an iron-sulfur cluster which, in the reduced [4Fe-4S](+) form, serves to reduce S-adenosylmethionine and to generate a catalytically essential glycyl radical. The reaction of the reduced cluster with oxygen was studied by UV-visible, EPR, NMR, and Mössbauer spectroscopies. The [4Fe-4S](+) form is shown to be extremely sensitive to oxygen and converted to [4Fe-4S](2+), [3Fe-4S](+/0), and to the stable [2Fe-2S](2+) form. It is remarkable that the oxidized protein retains full activity. This is probably due to the fact that during reduction, required for activity, the iron atoms, from 2Fe and 3Fe clusters, readily reassemble to generate an active [4Fe-4S] center. This property is discussed as a possible protective mechanism of the enzyme during transient exposure to air. Furthermore, the [2Fe-2S] form of the protein can be converted into a [3Fe-4S] form during chromatography on dATP-Sepharose, explaining why previous preparations of the enzyme were shown to contain large amounts of such a 3Fe cluster. This is the first report of a 2Fe to 3Fe cluster conversion.

Anaerobiosis↗
PubMed1999

[Is there a need for treatment in subclinical hypo- and hyperthyroidism?].

Subclinical thyroid dysfunction is characterized by normal levels of thyroid hormones but abnormal values of thyrotropin (TSH) in an asymptomatic individual. Subclinical hypothyroidism is a common disorder with a prevalence of about 7 to 8% in women (most frequently in females over 50 years), and about 3% in men. It is characterized by elevated serum TSH in the presence of normal concentrations of serum thyroxine. Patients with TSH levels about 12 mU/L (and with positive antithyroidal antibodies) have the highest risk for developing overt hypothyroidism. Therefore, these patients will require L-thyroxine treatment. In patients with TSH < 12 mU/L, the indication for therapy depends on the etiology, on risk factors and concomitant diseases (e.g. strumectomy, coronary heart disease, depression, infertility). Subclinical hyperthyroidism (TSH suppression syndrome) is characterized by normal thyroid hormone concentrations but diminished serum TSH. Most frequently, this disorder is caused by exogenous L-thyroxine treatment. The endogenous form of subclinical hyperthyroidism mainly caused by nodular goiter has a prevalence of up to 20% in patients with large goiters. In patients with subclinical hyperthyroidism, there is an increased risk for development of atrial fibrillation and for a decrease in bone mass in postmenopausal women. In the majority of patients measurable TSH levels can be detected before or after stimulation with TRH. This formally excludes overt hyperthyroidism in such patients. Frequently, there is no need for treatment but follow-up is important. However, in patients with subclinical hyperthyroidism associated with atrial fibrillation a therapy with antithyroid drugs, beta-blockers or radioiodine must be considered.

Diagnosis, Differential↗
PubMed1999

[Extraovarian peritoneal serous papillary carcinoma: an unusual surgical case].

The extraovarian peritoneal serous papillary carcinoma (EPSPC) is a multicentric peritoneal tumor with minimal or absent involvement of the ovaries. The actual treatment regimen consists of a cytoreductive surgery followed by a combination chemotherapy. Few studies have compared outcome of EPSPC to papillary serous ovarian cancer (PSOC). Several authors have documented similar clinical behavior between EPSPC and PSOC, but this finding has not been universal. A 64-year-old female patient with symptomatic gall stone disease underwent elective laparoscopic cholecystectomy. Unexpectedly we found some uncommon small nodular structures on the serosa of the right colon. The histological findings suggested a poorly differentiated peritoneal serous papillary carcinoma. Biopsies of both ovaries showed no signs of tumor infiltration and the diagnosis of EPSPC was established. After surgery, a combination chemotherapeutic regimen with carboplatin and cyclophosphamid was given. Laparoscopic reassessment 7 months after the first procedure showed no tumor. 3 identical cycles completed chemotherapy. Normal ovaries and no other tumor sites were found in a final laparoscopic look after 11 months.

Cystadenocarcinoma, Papillary↗