Biomedical subjects

C Meier

Publications and source records attributed to C Meier.

At least 55 records · Page 3Linked to original sources

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↗

PubMed1999

Luminal heterodimeric amino acid transporter defective in cystinuria.

Mutations of the glycoprotein rBAT cause cystinuria type I, an autosomal recessive failure of dibasic amino acid transport (b(0,+) type) across luminal membranes of intestine and kidney cells. Here we identify the permease-like protein b(0,+)AT as the catalytic subunit that associates by a disulfide bond with rBAT to form a hetero-oligomeric b(0,+) amino acid transporter complex. We demonstrate its b(0,+)-type amino acid transport kinetics using a heterodimeric fusion construct and show its luminal brush border localization in kidney proximal tubule. These biochemical, transport, and localization characteristics as well as the chromosomal localization on 19q support the notion that the b(0,+)AT protein is the product of the gene defective in non-type I cystinuria.

Amino Acid Sequence↗

PubMed1999

Intracellular metabolism of CycloSaligenyl 3'-azido-2', 3'-dideoxythymidine monophosphate, a prodrug of 3'-azido-2', 3'-dideoxythymidine (zidovudine).

The administration of CycloSaligenyl 3'-azido-2',3'-dideoxythymidine monophosphate (CycloSal-AZTMP) to CEM cells resulted in a concentration- and time-dependent conversion to the 5'-monophosphate (AZTMP), 5'-diphosphate (AZTDP), and 5'-triphosphate (AZTTP) derivatives. High ratios of AZTMP/AZTTP were found in the CEM cell cultures treated with CycloSal-AZTMP. The intracellular T(1/2) of AZTTP in CEM cell cultures treated with either AZT and CycloSal-AZTMP was approximately 3 h. A variety of human T- and B-lymphocyte cell lines efficiently converted the prodrug to the AZT metabolites, whereas peripheral blood lymphocytes and primary monocyte/macrophages showed at least 10-fold lower metabolic conversion of the prodrug. CycloSal-AZTMP failed to generate marked levels of AZT metabolites in thymidine kinase-deficient CEM/TK(-) cells, an observation that is in agreement with the substantial loss of antiviral activity of CycloSal-AZTMP in CEM/TK(-) cells. The inability of CycloSal-AZTMP to generate AZTMP in CEM/TK(-) cells is presumably due to a relatively high hydrolysis rate of AZTMP to the parent nucleoside AZT, combined with the inability of CEM/TK(-) cells to phosphorylate AZT to AZTMP through the cytosolic salvage enzyme thymidine kinase.

Anti-HIV Agents↗

PubMed1999

Screening methods for thyroid hormone disruptors.

The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. Participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen.

Animals↗

PubMed1999

Total serum bile acid concentrations in dairy cows with fatty liver and liver failure.

In forty-five Holstein Frisian dairy cows (1-6 weeks post partum; mean age: 5.1 +/- 1.2 years) the serum total bile acid concentrations (SBA) were measured enzymatically. In all cows a left sided abomasal displacement was corrected surgically by right side laparotomy and omentopexy three days before investigation. The liver fat content was determined in all cows histologically. Liver failure was assumed if typical clinical signs (ataxia, general depression, recumbency or coma), an increased venous plasma ammonia level (> 35 mumol/l) and a decreased plasma amino acid index (< 4.0) were found. Cows without liver failure (N = 29) were grouped according to the liver fat content as cows with mild (N = 5), moderate (N = 19) or severe hepatosteatosis (N = 5). Histological examination of liver biopsies in cows with liver failure (N = 16) revealed in twelve cases a severe fatty liver and in four cases a hydropic degeneration of the liver tissue. Although in cows without liver failure mean SBA concentrations were higher in the group with moderate (47.3 +/- 30.9 mumol/l) or severe fatty liver (32.9 +/- 21.7 mumol/l) than in that with mild lipidosis (18.0 (16.8 mumol/l), differences were not significant. The mean SBA concentration in cows with liver failure (70.5 +/- 49.5 mumol/l) was only significantly (p < 0.05) increased compared to cows with uncomplicated mild hepatic lipidosis. In conclusion, the determination of SBA concentrations is of little value in the recognition of fatty liver or even liver failure due to the considerable variance of SBA concentrations in dairy cows.

Abomasum↗

PubMed1998

[Long-term study of subclinical hypothyroidism: spontaneous course and predictors of manifest hypothyroidism].

The syndrome of subclinical hypothyroidism is frequent and predominantly affects females over 40. Only limited data on its natural course is available. It was the aim of our prospective trial to analyze the spontaneous evolution of this syndrome, to identify risk factors of the development of overt hypothyroidism and to develop guidelines for the management of such patients. 154 female patients were followed over a mean observation period of 10 years. After 10 years, 34% had developed overt hypothyroidism, 57% remained in the subclinical stage, and in 9% thyroid function had normalized. The initial grading of TSH-concentration (< 6 mU/l, 6-12 mU/l, > 12 mU/l) was highly predictive for thyroid failure: 7.3%, 25% and 78%, respectively, overt hypothyroidism occurred. Further risk factors for thyroid failure included an impaired thyroid reserve (T3-stimulation after TRH) and elevated titers of microsomal antibodies. We therefore recommend to controlling patients with a TSH-concentration < 6 mU/l, start thyroxine hormone replacement therapy in patients with a TSH-concentration > 12 mU/l and, depending on the additional risk factors, either controlling or treating patients with a TSH-concentration of 6-12 mU/l.

Adolescent↗

PubMed1998

cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system.

The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-d4TMP derivatives 3a-h of the anti-HIV dideoxynucleoside 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, 1) are reported. This pro-nucleotide concept has been designed to deliver d4TMP (2) by selective chemical hydrolysis. All compounds 3a-h were synthesized using phosphorus(III) chemistry in good yields and in somewhat lower yields using phosphorus(V) chemistry starting from substituted salicyl alcohols 6a-h. The phosphotriesters 3 were obtained without stereochemical preference with respect to the configuration at the phosphorus center as 1:1 diastereomeric mixtures. However, a few of the triesters 3 could be separated into the diastereomers by means of semipreparative HPLC. In a 1-octanol/phosphate buffer mixture, all compounds 3 exhibited 9-100-fold higher lipophilicity as judged from their Pa values as compared to d4T (1). Furthermore, in hydrolysis studies 3 decomposed under mild aqueous basic conditions releasing solely d4TMP (2) and the diols 6 following the designed tandem reaction sequence. A correlation of the electronic properties introduced by the substituents and the half-lives of triesters 3 was observed. Thus, by varying the substituent, the half-lives of 3 could be adjusted over a wide range of compounds still delivering d4TMP (2) selectively. Phosphotriesters 3 exhibited considerable activity against HIV-1 and HIV-2 in wild-type human T-lymphocyte (CEM/O) cells as well as mutant thymidine kinase-deficient (CEM/TK-) cells. Surprisingly, we observed a 3-80-fold difference in antiviral activity between the two diastereomers. Our data clearly prove that the cycloSal-d4TMPs deliver exclusively the nucleotide d4TMP not only under simulated hydrolysis conditions but also under cellular conditions and thus fulfill the thymidine kinase-bypass premise. Therefore, the cycloSal-nucleotide concept is the first reported pro-nucleotide system that delivers the dideoxynucleotide by a pH-driven, chemically activated, tandem reaction without the requirement of an enzymatic contribution.

Animals↗

PubMed1998

[Ultrasensitive TSH screening for detection of thyroid gland dysfunctions in women of a medical ambulatory care patient group].

This aim of the study was to identify the prevalence of unsuspected thyroid dysfunction in a female population attending a medical primary care unit (case-finding study). A TSH assay of the third generation was used as a screening test. The overall prevalence of unsuspected thyroid dysfunction in 1061 female patients was 2.5% (0.5% overt hyperthyroidism, 0.3% overt hypothyroidism, 0.5% subclinical hyperthyroidism, and 1.2% subclinical hypothyroidism). The prevalence of thyroid disease is clearly age dependent with 4.3% over the age of 40 and 5.9% for 50-60 year-olds. The ratio for females below 40 and over 40 was 10.75 (Odds ratio, p < 0.0001). We conclude from our study and from the literature that TSH screening as a case-finding strategy is indicated, and also seems cost-effective, in women over 40 years of age.

Adolescent↗

PubMed1998

Sexual victimization in adolescent girls (age 15-20 years) enrolled in post-mandatory schools or professional training programmes in Switzerland.

An analysis of data from the Swiss Multicenter Adolescent Survey on Health was conducted to assess the prevalence of a history of sexual victimization among a national sample of adolescent girls enrolled in schools or professional training, to estimate the number of associated psychosocial health problems, and to gain information on the effects of disclosure of the experience. A representative sample of 9268 adolescents answered a written questionnaire on health and lifestyle. Of the 3993 participating girls, 18.6% reported an experience of sexual victimization. The burden of associated psychosocial health problems was considerable, notably as regards depression, suicidal behaviour and substance misuse. Preliminary findings on the relation of disclosure and mechanisms of learned helplessness stress the need for more research on this issue. The results stress the importance of prevention programmes for adolescents and preadolescents, of physicians' awareness and training for screening and appropriate counselling, and of easy access to professional support.

Adolescent↗

PubMed1998

The p68 autoantigen characteristic of rheumatoid arthritis is reactive with carbohydrate epitope specific autoantibodies.

OBJECTIVE: The autoantigen p68 is a target of autoantibodies as well as autoreactive T cells with a high specificity in rheumatoid arthritis (RA). The binding characteristics of the autoantibodies to their antigen were now analysed biochemically and cytologically. METHODS: Deglycosylation techniques as well as lectin and sugar competition experiments were performed to p68 to discover if the antibodies detected a glycoepitope, Its antigenicity was investigated applying anti-p68 antibodies derived from RA patients in comparison with polyclonal rabbit anti-p68 antibodies. RESULTS: p68 specific antibodies from RA patients did not to bind to p68 that had been deglycosylated by alkaline beta-elimination, O-glycosidase or periodate treatment. In contrast, binding of p68 specific antibodies raised in rabbit was unaffected by either deglycosylation protocol. Furthermore, lectins specific for the carbohydrate N-acetylglucosamine competed with p68 specific antibodies from RA patients for antigen bindings. N-acetylglucosamine by itself also competed with patient derived anti-p68 antibodies for p68 binding. Again, rabbit and anti-p68 antibodies did not elicit these competitive effects. Applying cytoimmunofluorescence, p68 was present in the cytoplasm or endoplasmic reticulum and also in low abundance on the cell surface. Under heatshock conditions, p68 was detectable in the nucleus. CONCLUSIONS: Autoimmunity to p68 during RA is carried by anti-carbohydrate autoantibodies. The carbohydrate modification of p68 appears to be N-acetylglucosamine, which may reflect the regulation of intracellular localisation of the antigen. It is hypothesised that a shift in glycosylation pattern accompanied by an unphysiological localisation of the antigen could trigger antigenicity of p68 during the pathogenesis of IRA.

Arthritis, Rheumatoid↗

PubMed1998

Synthesis and antiviral evaluation of SATE-foscarnet prodrugs and new foscarnet-AZT conjugates.

The synthesis of a range of di- and triester derivatives of phosphonoformate (PFA; foscarnet) as potential lipophilic, membrane-soluble prodrugs is described. In addition to normal alkyl esters in the carboxylate and phosphonate residues of PFA, the bioreversible S-(pivaloyl)thioethyl (t-butyl-SATE) group was introduced in an attempt to deliver PFA after bioactivation inside the cells. Furthermore, PFA-AZT conjugates were prepared in order to develop combinational drugs. The key synthetic step was in all cases the formation of the P-C bond to build up the different PFA esters. In contrast to the diester derivatives, the triesters of PFA showed high hydrolytic instability during chromatographic purification. The compounds were evaluated in vitro for their ability to inhibit viruses in several tissue culture systems. All PFA alkyl di- and triesters proved poorly active or inactive against human immunodeficiency virus (HIV) and inactive against hepatitis B virus. In contrast, the PFA-AZT conjugates exhibited significant anti-HIV activity. However, this activity was nearly completely lost in thymidine kinase-deficient cells, suggesting a fast unselective chemical hydrolysis of the conjugates to yield the nucleoside analogue AZT in the cell culture medium. Furthermore, no synergistic effect of PFA and AZT was observed.

Anti-HIV Agents↗

PubMed1998

Chemistry and anti-herpes simplex virus type 1 evaluation of cycloSal-nucleotides of acyclic nucleoside analogues.

The synthesis of different cycloSal-phosphotriesters of the acyclic nucleoside analogues acyclovir (ACV), penciclovir (PCV) and T-penciclovir (T-PCV) as potential new lipophilic, membrane-soluble pronucleotides is described. The introduction of the cycloSal moiety was achieved by using reactive cyclic chlorophosphane reagents. In addition to the cycloSal-PCV monophosphate (MP) phosphotriesters, a second derivative bearing an acetyl group at the second primary alcohol function was prepared. In hydrolysis studies the cycloSal-ACVMPs showed the expected range of hydrolytic stability dependent on the substituent in the masking group (8-17 h). In contrast, the cycloSal-PCVMP derivatives exhibited a 11- to 15-fold increase in hydrolytic lability as compared to the corresponding cycloSal-ACVMP derivatives. We demonstrated that the free primary alcohol group is responsible for this rate acceleration because cycloSal-OAc-PCVMP, in which the hydroxyl group was blocked by acetylation, did not show the aforementioned acceleration. Unexpectedly, the hydrolysis product was not PCVMP but according to NMR and mass spectrometry it was cycloPCVMP (cPCVMP). The title compounds were evaluated in vitro for their ability to inhibit herpes simplex virus type 1 (HSV-1) and thymidine kinase-negative (TK-) HSV-1 replication in Vero cells. The cycloSal-ACVMP compounds exhibited high antiviral activity in HSV-1-infected cells. More importantly, one derivative retained all activity from the wild-type virus strain in HSV-1/TK(-)-infected Vero cells. The PCV derivatives were markedly less active. The reason for the failure of the cycloSal-PCVMPs seems to be due to the formation of cPCVMP instead of the desired PCVMP.

Acyclovir↗

PubMed1997

[Clinical value of C-peptide determination].

The classification of newly diagnosed diabetic patients as type I (insulin-dependent) or type II (non-insulin-dependent) diabetes and the implied therapeutical consequences there of are based on clinical observations and laboratory tests. In case differential diagnosis is difficult, the measurement of the c-peptide secretion to assess beta-cell capacity can be helpful. For adequate control especially after long-standing diabetes in obese patients it is important to identify patients with potential secondary drug failure. Poor compliance with diet is thought to be a major reason for poor response to treatment. On the other hand, diabetics with poor control because of deterioration of beta-cell function must be distinguished. In these situations the measurement of c-peptide concentrations may contribute to identify the need for insulin treatment. As a result the development of diabetic complications can be retarded and beta-cell function can be preserved by adequate insulin therapy, whereas the consequences of hyperinsulinaemia in insulin treated patients not needing insulin can be avoided. In our opinion the c-peptide/glucose-quotient serves as simple, cost-effective and non-invasive method in the assessment of beta-cell capacity. Insulin therapy is indispensable in the case of inadequate insulin secretion.

Aged↗

PubMed1997

A perspective from clinical and business ethics on adverse events in hospitalized patients.

Adverse events occur in a significant, but undetermined, number of hospitalized patients. These types of patient injuries are more often the result of faulty systems than human maleficence. A culture exists among health care providers that discourages the reporting of such events and resists the implementation of formal efforts to eliminate them. This resistance serves to perpetuate the problem. Both business and clinical ethics argue that sound reasons exist for hospitals to reduce, if not eliminate, adverse events. To do so is cost effective, particularly in a managed care environment. It is also at the heart of responsible professional behavior. Physicians are afforded an opportunity to be at the forefront in this quality improvement effort.

Accidents↗

PubMed1996

Oct-6 (SCIP/Tst-1) is expressed in Schwann cell precursors, embryonic Schwann cells, and postnatal myelinating Schwann cells: comparison with Oct-1, Krox-20, and Pax-3.

The POU domain transcription factor Oct-6 (SCIP/Tst-1) is likely to control important stages of Schwann cell development, including the initiation of myelination around birth. Here, we use immunocytochemical and reverse transcriptase-polymerase chain reaction techniques to examine Oct-6 earlier in nerve development, to test the idea that Oct-6 has an additional role in Schwann cell precursors or early embryonic Schwann cells, a possibility raised by previous studies on transgenic mice. Consistent with this, we find low but unambiguous levels of Oct-6 mRNA and protein in Schwann cell precursors of mouse and rat (nerves from 12- and 14-day-old embryos, respectively), with expression levels gradually increasing during early Schwann cell development and towards birth. Unexpectedly, Oct-6 immunoreactivity is clearly present in nuclei of most myelinating cells at least as late as postnatal day 12. Furthermore, many nonmyelinating Schwann cells express Oct-6 in adult life. A comparison of Oct-6 mRNA with other Schwann cell transcription factors-namely, Oct-1, Krox-20, and Pax-3-reveals that each factor exhibits strong developmental regulation and a unique expression pattern in embryonic nerves. Therefore, they are likely to play distinct regulatory roles in early development of the Schwann cell lineage.

Animals↗

PubMed1996

[A clinical-pharmacological case (1). Action of cisapride (Prepulsid) on bladder function].

We report the case of a 75 old man with chronic constipation due to traumatic spinal cord injury 25 years ago. Following prostatectomy the patient developed retention of urine and urinary incontinence, which improved significantly during a therapy with cisapride (3 x 10 mg/day). While the administration of cisapride is associated with increased detrusor activity and possibly urinary incontinence in neurologically normal persons, patients with urinary retention due to spinal cord injury may benefit from a therapy with this indirect parasympathomimetic agent.

Aged↗