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Biomedical subjects

M Meyer

Publications and source records attributed to M Meyer.

At least 91 records · Page 5Linked to original sources
PubMed2001

Differentiation of embryonic stem cell-derived dopaminergic neurons is enhanced by survival-promoting factors.

Here, we describe the generation of viable and dopamine-producing neurons derived from pluripotent mouse embryonic stem cells. Neurotrophic factors in combination with survival-promoting factors, such as interleukin-1beta, glial cell line-derived neurotrophic factor, neurturin, transforming growth factor-beta(3) and dibutyryl-cyclic AMP, significantly enhanced Nurr1 and tyrosine hydroxylase (TH) mRNA levels, whereas En-1, mash-1 and dopamine-2-receptor mRNA levels were not upregulated. In parallel, mRNA levels of the anti-apoptotic gene bcl-2 were found to be upregulated at terminal stages. Double immunofluorescence analysis revealed increased numbers of TH- and dopamine transporter-, but not gamma-aminobutyric acid- and serotonin-positive neurons in relation to synaptophysin-labeled cells by survival-promoting factors. Moreover, high-performance liquid chromatography analysis showed detectable levels of intracellular dopamine. We conclude that survival-promoting factors enhance differentiation, survival and maintenance of dopaminergic neurons derived from embryonic stem cells.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Chronic oral administration of CI-994: a phase 1 study.

OBJECTIVES: CI-994 (N-acetyl dinaline, PD 123654) is a novel oral agent active in a broad variety of murine and human tumor xenografts. While cytotoxic in the Brown Norway (BN) rat leukemia model, growth inhibition in other murine and human tumor xenografts is predominantly cytostatic. Its specific mechanism of action remains unknown. Following CI-994 administration, inhibition of both histone deacetylation and cellular proliferation at the G1 to S transition phase of the cell cycle are observed. This Phase 1 study in patients with solid tumors was carried out to determine a maximum tolerated daily oral dose (MTD) for CI-994 administered on a chronic basis. METHODS: Fifty-three patients received CI-994 daily for treatment durations ranging from 2 to 10 weeks. Dosage escalation proceeded in 2 phases; an Acute Dosing Phase (n = 11) to define the MTD for CI-994 administered over 2 weeks and a Chronic Dosing Phase (n = 29) to define the MTD for daily administration for 8 weeks. Upon completion of the Chronic Dosing Phase, a third cohort of patients (n = 13) received CI-994 at the recommended Phase 2 dose and schedule with 2 additional single doses of drug administered separated by a 1-week washout to assess the effect of food on CI-994 pharmacokinetics. RESULTS: Thrombocytopenia was dose limiting at the MTD of 8 mg/m2/day for 8 weeks. Other toxicities included fatigue and gastrointestinal effects such as nausea, vomiting, diarrhea, constipation and mucositis. Pharmacokinetic studies revealed that peak plasma levels and AUC's generally increased with dose and that food intake did not affect the rate or extent of drug absorption. One patient with heavily pre-treated adenocarcinoma of the lung achieved a Partial Response (PR) lasting over 2 years and 3 additional patients achieved Stable Disease (SD), 1 each with non-small cell lung, colorectal, and renal cancer. CONCLUSIONS: The recommended Phase 2 starting dose is 8 mg/m2/day for 8 weeks repeated after a 2-week drug-free interval.

Administration, Oral↗
PubMed2001

Overdenture attachment selection and the loading of implant and denture-bearing area. Part 1: In vivo verification of stereolithographic model.

Preliminary to a study investigating the force transfer from osseointegrated dental implants to the surrounding bone via various types of overdenture attachment, a stereolithographic model (SL-model) was constructed and compared to an in vivo situation in order to confirm the validity of the modeling technique for the planned measurements of implant strain and denture-bearing area loading. The SL-model was generated using the patient's computer tomographic data and duplicated in a material of known elastic properties. The model was fitted with sensors to measure strains in the peri-implant bone and loading forces within the posterior mandibular bone, i.e. the denture-bearing area of the mandible. Special telescopic copings were constructed to measure implant strain in this model as well as in vivo. Using these copings under identical overdenture loading conditions, the strains measured at the implants in vivo and in vitro were the same and never exceeded a tolerance of two standard deviations or a mean difference of -8.5% of the in vitro value. This indicates that the model was reliable for the measurement of implant strain. Denture-bearing area loading within the alveolar ridge cannot be measured in vivo. Instead, a method of extrapolating in vivo denture-bearing area loading figures from implant strain readings was developed and tested (better than 90% accuracy). These in vivo extrapolated figures were then compared to in vitro readings under otherwise identical loading conditions. The result indicated that the SL-model is reliable for measurements of denture-bearing area loading with an error of 10 to 20%.

Calibration↗
PubMed2001

Overdenture attachment selection and the loading of implant and denture-bearing area. Part 2: A methodical study using five types of attachment.

In general, an implant is loaded via axial and horizontal forces. Besides this, moment loading can also occur. The aim of this study was to investigate how different prosthetic connectors with overdentures develop force transfer to implant and bone as well as to the denture-bearing alveolar ridge. Five connectors were investigated on a stereolithographic model fabricated according to a real patient situation. The model was fitted with strain gauges on the "bone" distal and medial to the implants and with vertical force transducers in the alveolar "bone" under the denture-bearing area. The parallel-sided rigid telescopic connector developed the highest moment loading of the implant (P<0.001), which would suggest restraint in the use of this connector. The bar construction also showed somewhat high moments but these may have been at least partly exaggerated by the individual patient situation. Loading results through the non-rigid telescopic copings, single spherical attachments and magnet overdentures demonstrated a low level of implant moment loading which would in part result from horizontal forces caused by denture forward shift during force application. The denture-bearing area loading was different with all attachments (P<0.001) and was related to the rigidity of the connector and reached the highest values with the non-rigid telescopic coping. The clinical implications of the various findings are discussed.

Alveolar Process↗
PubMed2001

Neurotrophins are required for nerve growth during development.

Although the requirement of neurotrophins for the prevention of cell death in the peripheral nervous system is well established, their physiological involvement in nerve growth is still unclear. To address this question, we generated a mouse that expresses the green fluorescent protein in post-mitotic neurons, allowing the repeated visualization of all motor and sensory axons during development. We imaged the growth of these axons into the limb bud of day 10.5 embryos. Sensory axons, but rarely motor axons, were targeted to ectopically placed beads containing any of the neurotrophins NGF, BDNF, NT-3 or NT-4/5. Conversely, a combination of function-blocking monoclonal antibodies to NGF, BDNF and NT-3 dramatically inhibited elongation of both sensory and motor axons in the limb bud, indicating that the growth of mixed nerves is dependent upon neurotrophins during development.

Animals↗
PubMed2001

Thermodynamic and kinetic issues in the formation and oxidation of aromatic species.

The chemistry of aromatic species is discussed in the context of detailed kinetic modelling of benzene and butadiene flames and stirred reactors featuring ethylene and mixed aromatic/ethylene/hydrogen fuels. The development of reliable detailed mechanisms depends on the accuracy of the underlying hydrocarbon chemistry and the present paper highlights some current issues in the formation and oxidation of aromatics. In particular, uncertainties pertaining to the rates and product distributions of a range of possible naphthalene and indene formation sequences are discussed from the basis of improved predictions of key intermediates. The naphthalene formation paths considered include initiation via C5H5 + C5H5, C6H5 + C4H4 and C7H7 + C3H3 reactions and results are assessed in the context of a number of tentative detailed and simplified sequences. It is shown that a number of possible formation channels are plausible and that their relative importance is strongly dependent upon oxidation conditions. Particular emphasis is placed on the investigation of formation paths leading to isomeric C9H8 structures. The latter are typically ignored despite measured concentrations similar to those of naphthalene. The rates of formation of C9H8 compounds are consistent with sequences initiated by C6H5 + C3H3 and C6H5 + C3H4 leading to indene through repeated isomerisation reactions. The current work also shows that reactions of the type C9H7 + CH3 and C9H7 + 3CH2 provide a mass growth source that link five and six member ring structures.

Journal Article↗
PubMed2001

A noninvasive test for vesico-ureteric reflux in children.

OBJECTIVE: To report the development and testing of a device for the noninvasive diagnosis of vesico-ureteric reflux (VUR) which avoids the need for urethral catheterization (currently required to reliably determine the presence of VUR), and which thus avoids the anxiety of parents and patients that causes many families to refuse such evaluation. PATIENTS AND METHODS: Fifty-four children (49 girls and five boys, mean age 7.2 years, range 4-14) previously evaluated as having VUR volunteered to participate; no child was symptomatic at the time of the study. Refluxing units were known to be present by voiding cysto-urethrography (within 1 year, mean 7 months) in 45 and absent in 16. The device developed acquires electronically processed acoustic signals from the child during an observed urination. The signals are then analysed 'off-line' to determine the presence or absence of VUR. The initial preparation for the test included: (i) a full bladder [at least 0.80 x ((2 + age) x 30 mL)] measured by ultrasonography; and (ii) localization of the pelvi-ureteric junction by ultrasonography to accurately place the device's sensors on the child's back. The children were then positioned at a commode after placing the sensors; the recording was started and continued until voiding occurred. The children were tested with the recording and analysis team unaware of the presence and/or degree of VUR. The first 47 studies were single-kidney examinations and the remaining seven included simultaneous monitoring of both kidneys. RESULTS: Sixty-one renal units were assessed and interpretable signals were obtained from 54 (89%). There were seven episodes of 'system failure' when no interpretable data were obtained. One unit with no VUR had a 'reflux' signal; in four kidneys, spontaneous (two) and postsurgical (two) resolution of reflux was predicted by the testing and subsequently verified by cyclic radionuclide cystography. CONCLUSIONS: This noninvasive diagnostic technique detected VUR in 35 of 37 refluxing units and verified no reflux in 16 of 17 units without VUR. Further refinements may allow this technology to be used in all children with suspected VUR.

Adolescent↗
PubMed2001

Efficacy and tolerability of racecadotril in acute diarrhea in children.

BACKGROUND & AIMS: Oral rehydration therapy is the only treatment recommended by the World Health Organization in acute diarrhea in children. Antisecretory drugs available could not be used because of their side effects, except for racecadotril, which is efficient in acute diarrhea in adults. METHODS: The efficacy and tolerability of racecadotril (1.5 mg/kg administered orally 3 times daily) as adjuvant therapy to oral rehydration were compared with those of placebo in 172 infants aged 3 months to 4 years (mean age, 12.8 months) who had acute diarrhea. The treatment groups were comparable in terms of age, duration of diarrhea, number of stools, and causative microorganism at inclusion. RESULTS: During the first 48 hours of treatment, patients receiving racecadotril had a significantly lower stool output (grams per hour) than those receiving placebo. The 95% confidence interval was 43%-88% for the full data set (n = 166; P = 0.009) and 33%-75% for the per-protocol population (n = 116; P = 0.001). There was no difference between treatments depending on rotavirus status. Significant differences between treatment groups were also found after 24 hours of treatment: full data set (n = 167; P = 0.026) and per-protocol population (n = 121; P = 0.015). Tolerability was good in both groups of patients. CONCLUSIONS: This study demonstrates the efficacy (up to 50% reduction in stool output) and tolerability of racecadotril as adjuvant therapy to oral rehydration solution in the treatment of severe diarrhea in infants and children.

Acute Disease↗
PubMed2001

Latrogenic tracheobronchial lesions--a report on 13 cases.

BACKGROUND: Tracheobronchial ruptures are occurrences which mainly result from blunt or penetrating neck or thoracic trauma, but also from long-term complications of intubation or tracheostomy. Acute iatrogenic tracheobronchial lesions are very uncommon. METHODS: From February 1995 to July 1998, we treated 13 patients (12 female, 1 male, mean age 68 years, range 45-86) in our institution for iatrogenic tracheobronchial injuries after single lumen intubation (n = 8), double lumen intubation (n = 4), and tracheostomy (n = 1). We retrospectively analyzed the medical records of these patients concerning age, sex, symptoms, endoscopic and intraoperative findings, treatment and outcome. RESULTS: All patients underwent surgical treatment via right-sided thoracotomy. In the cases of 11 patients, repeated postoperative bronchoscopy revealed sufficient reconstruction of the lesions. Nevertheless, only 5 patients survived. The remainder died of the sequelae of trauma-related hypoxia, underlying (malignant) diseases, or of septic multiorgan failure after a median of 15 days (1 hour to 27 days). CONCLUSIONS: While technical problems of tracheobronchial reconstruction in our series were controllable, the long-term results were not satisfying. Our data suggest that the key for better outcome of these kind of lesions lies in an early diagnosis and immediate treatment, thus keeping the trauma-treatment interval with the concomitant hypoxic damage as short as possible.

Aged↗
PubMed2001

Quantum-chemical analysis of C-H...O and C-H...N interactions in RNA base pairs--H-bond versus anti-H-bond pattern.

Geometries and interaction energies of unusual UU and AA base pairs with one standard hydrogen bond (H-bond) and additional C-H...O or C-H...N contacts have been determined by quantum-chemical methods taking into account electron correlation. Whereas the C-H bond length in the UU C-H...O contact increases upon complex formation (H-bond pattern), the C-H bond of the AA C-H....N interaction is shortened (anti-H-bond pattern). The same properties are found for model complexes between U or A and formaldehyde that have intermolecular C-H...acceptor contacts but no standard H-bonds. Both the C-H...acceptor H-bond and anti-H-bond interactions are attractive. A possible influence of the donor CH group charge distribution on the interaction pattern is discussed.

Adenine↗
PubMed2001

Phase 1 drug interaction study of suramin and warfarin in patients with prostate cancer.

Potential interaction between suramin and warfarin was evaluated when coadministered to patients with cancer. Thirteen men with advanced hormone-refractory prostate cancer were initially stabilized with warfarin to a prothrombin time (PT) of 2 +/- 0.2 International Normalized Ratio (INR) during a lead-in period of 4 weeks. A baseline daily warfarin dose was established, and treatment with suramin plus hydrocortisone was then started. The effect of suramin on the anticoagulant activity of warfarin was assessed in each patient by comparing his baseline warfarin dose with average daily doses required to maintain the same INR level over each of the initial 6 weeks of a 12-week course of suramin treatment. The average daily dose of warfarin required to maintain PT at 2 +/- 0.2 INR decreased from a baseline value of 4.2 to between 3.4 and 4.0 during the 6 weeks of suramin plus warfarin treatment. Despite failing to demonstrate equivalence applying a 90% confidence interval approach, required reductions in warfarin dose were clinically minor and the combination was well tolerated. Based on these results, the eligibility criteria for a large ongoing randomized study were amended to allow entry of men receiving warfarin therapy. This interaction study, together with experience gained in a larger trial setting, has confirmed that warfarin and suramin can be safely coadministered, provided that coagulation status is appropriately monitored.

Anti-Inflammatory Agents↗
PubMed2001

Apolipoprotein B Arg3500Gln mutation prevalence in children with hypercholesterolemia: a French multicenter study.

BACKGROUND: Familial defective apolipoprotein B-100, a dominantly inherited form of hypercholesterolemia caused by a single Arg3500Gln mutation, is silent in childhood but may confer a high risk of cardiovascular disease in adulthood. The objective was to determine the prevalence of familial defective apolipoprotein B-100 in hypercholesterolemic French children and to provide a basis for targeting screening efforts in this population. METHODS: One hundred ninety children attending 13 pediatric clinics distributed throughout France were included based on the presence of type IIa hypercholesterolemia with a plasma low-density lipoprotein-cholesterol level of more than 130 mg/dL. The Arg3500Gln mutation was detected in dried blood spots using a polymerase chain reaction assay combined with enzymatic restriction. RESULTS: Three hyperlipidemia phenotypes were found: monogenic dominant pure hypercholesterolemia (n = 117), polygenic hypercholesterolemia (n = 43), and combined hyperlipidemia (n = 11). Three unrelated children were heterozygous for the Arg3500Gln mutation; all three had monogenic dominant pure hypercholesterolemia (3/94 families; 3.2%), yielding a prevalence of 1.83% (3/164) in hypercholesterolemic children, which is similar to prevalences reported in European adults. CONCLUSIONS: The familial defective apolipoprotein B-100 mutation was common (1/31) in children with a phenotype of familial hypercholesterolemia, supporting screening in this population with the goal of preventing premature cardiovascular events.

Adolescent↗
PubMed2001

Catabolite repression of the citrate fermentation genes in Klebsiella pneumoniae: evidence for involvement of the cyclic AMP receptor protein.

Klebsiella pneumoniae is able to grow anaerobically with citrate as a sole carbon and energy source by a fermentative pathway involving the Na(+)-dependent citrate carrier CitS, citrate lyase, and oxaloacetate decarboxylase. The corresponding genes are organized in the divergent citC and citS operons, whose expression is strictly dependent on the citrate-sensing CitA-CitB two-component system. Evidence is provided here that the citrate fermentation genes are subject to catabolite repression, since anaerobic cultivation with a mixture of citrate and glucose or citrate and gluconate resulted in diauxic growth. Glucose, gluconate, and also glycerol decreased the expression of a chromosomal citS-lacZ fusion by 60 to 75%, whereas a direct inhibition of the citrate fermentation enzymes was not observed. The purified cyclic AMP (cAMP) receptor protein (CRP) of K. pneumoniae bound to two sites in the citC-citS intergenic region, which were centered at position -41.5 upstream of the citC and citS transcriptional start sites. Binding was apparently stimulated by the response regulator CitB. These data indicate that catabolite repression of the citrate fermentation genes is exerted by CRP and that in the absence of repressing carbon sources the cAMP-CRP complex serves to enhance the basal, CitB-dependent transcription level.

Anaerobiosis↗
PubMed2001

Impaired sarcoplasmic reticulum function leads to contractile dysfunction and cardiac hypertrophy.

Sarcoplasmic reticulum (SR)-mediated Ca(2+) sequestration and release are important determinants of cardiac contractility. In end-stage heart failure SR dysfunction has been proposed to contribute to the impaired cardiac performance. In this study we tested the hypothesis that a targeted interference with SR function can be a primary cause of contractile impairment that in turn might alter cardiac gene expression and induce cardiac hypertrophy. To study this we developed a novel animal model in which ryanodine, a substance that alters SR Ca(2+) release, was added to the drinking water of mice. After 1 wk of treatment, in vivo hemodynamic measurements showed a 28% reduction in the maximum speed of contraction (+dP/dt(max)) and a 24% reduction in the maximum speed of relaxation (-dP/dt(max)). The slowing of cardiac relaxation was confirmed in isolated papillary muscles. The late phase of relaxation expressed as the time from 50% to 90% relaxation was prolonged by 22%. After 4 wk of ryanodine administration the animals had developed a significant cardiac hypertrophy that was most prominent in both atria (right atrium +115%, left atrium +100%, right ventricle +23%, and left ventricle +13%). This was accompanied by molecular changes including a threefold increase in atrial natriuretic factor mRNA and a sixfold increase in beta-myosin heavy chain mRNA. Sarcoplasmic endoplasmic reticulum Ca(2+) mRNA was reduced by 18%. These data suggest that selective impairment of SR function in vivo can induce changes in cardiac gene expression and promote cardiac growth.

Animals↗
PubMed2001

Intracellular accumulation of middle hepatitis B surface protein activates gene transcription.

While the natural intact protein does not possess any transactivator function, C-terminal truncation of the middle hepatitis B surface (MHBs) protein yields a novel transactivator function. We have previously found that the truncated transactivator protein, MHBs(t167), is not secreted but retained within the secretory pathway. Here, we provide evidence that when full-length MHBs is coexpressed with the truncated MHBs(t167) protein, the secretion of the full-length protein is inhibited and both proteins accumulate within the cell. We further show that MHBs, forcibly retained in the cell by C-terminal fusion to the endoplasmic reticulum retention signal KDEL (MHBsKDEL), mimics the effects of MHBs(t167) in enhancing the nuclear-binding activity of transcription factors NFkappaB and AP-1, and activation of NFkappaB- and AP-1-dependent transcription of reporter genes. As is the case for MHBs(t167), MHBsKDEL-dependent activation of NFkappaB is inhibited by the antioxidant N-acetyl-L-cysteine indicating the involvement of reactive oxygen intermediates and suggesting a similar mechanism of activation. This study suggests that the intracellular retention and accumulation of the normally secreted MHBs leads to oxidative stress and activation of transcription. This may be an important but not exclusive mechanism in hepatocarcinogenesis.

Carcinoma, Hepatocellular↗