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Biomedical subjects

M Weiss

Publications and source records attributed to M Weiss.

At least 199 records · Page 11Linked to original sources
PubMed1999

Wiskott-Aldrich syndrome protein regulates podosomes in primary human macrophages.

Wiskott-Aldrich syndrome protein (WASp) is a hematopoietic-specific, multidomain protein whose mutation is responsible for the immunodeficiency disorder Wiskott-Aldrich syndrome. WASp contains a binding motif for the Rho GTPase CDC42Hs as well as verprolin/cofilin-like actin-regulatory domains, but no specific actin structure regulated by CDC42Hs-WASp has been identified. We found that WASp colocalizes with CDC42Hs and actin in the core of podosomes, a highly dynamic adhesion structure of human blood-derived macrophages. Microinjection of constitutively active V12CDC42Hs or a constitutively active WASp fragment consisting of the verprolin/cofilin-like domains led to the disassemly of podosomes. Conversely, macrophages from patients expressing truncated forms of WASp completely lacked podosomes. These findings indicate that WASp controls podosome assembly and, in cooperation with CDC42Hs, podosome disassembly in primary human macrophages.

Actins↗
PubMed1999

MUC1 isoform specific monoclonal antibody 6E6/2 detects preferential expression of the novel MUC1/Y protein in breast and ovarian cancer.

The products of the MUC1 gene are known to be highly expressed in human breast cancer cells. The best characterized MUC1 protein is a polymorphic, type 1 transmembrane molecule containing a large extracellular domain composed primarily of a variable number of 20 amino acid tandem repeats. We have recently identified a novel protein product of the MUC1 gene, the MUC1/Y protein, that is also a transmembrane protein but is devoid of the tandem repeat array and its immediate flanking sequences. To analyze its expression in tumor cells we generated monoclonal antibodies directed against the MUC1/Y extracellular domain (anti-MUC1/Yex MAbs). Epitope mapping identified the MAb, 6E6, which recognized the MUC1/Y isoform with exquisite specificity- the repeat-array-containing MUC1 isoform could not compete out this immunoreactivity. A 30mer peptide which is unique for MUC1/Y and corresponds to the "join" region generated by the MUC1/Y specific splice, abrogated all 6E6 MAb immunoreactivity towards MUC1/Y. Immunoprecipitation of the MUC1/Y protein with 6E6 MAbs revealed that, in contrast with the proteolytic cleavage of the tandem-repeat-array-containing MUC1 isoform, MUC1/Y is not cleaved. Flow cytometry analyses using the 6E6 MAbs demonstrated that the MUC1/Y isoform is expressed on the cell surface of both MCF-7 breast cancer cells and malignant epithelial cells present in effusions obtained from breast and ovarian cancer patients. Our results unequivocally establish that the MUC1/Y protein is expressed on the surface of breast cancer cells and cells of other epithelial malignancies. The anti-MUC1/Y MAbs described here can target MUC1/Y expressing tumor cells in vivo and are likely to be important reagents both for epithelial tumor diagnosis and immunotherapy.

3T3 Cells↗
PubMed1999

Chronic poisoning by copper in tap water: I. Copper intoxications with predominantly gastointestinal symptoms.

Copper can induce acute and chronic intoxications in humans. Copper in tap water has caused a series of severe systemic diseases in Germany in recent years (copper induced liver cirrhosis). Besides cirrhosis, another type of disease with predominantly gastrointestinal symptoms has occurred which likewise appeared to be induced by copper in tap water. - In a retrospective investigation we looked for additional indications and proof that chronic copper poisoning has been the cause of the observed gastrointestinal diseases. All patients suffering from this type of disease had copper plumbing in their houses. - The patients (children and adults) suffered from nausea, vomiting, colic, and diarrhoea. In the group of infants, one refused formula milk (prepared with tap water) and the others suffered from persistent restlessness, unexplainable screaming (especially at night) and/or long lasting diaper rash. - We accept the diagnosis of chronic copper intoxication as the cause of the gastrointestinal symptoms when at least one of the following criteria were fulfilled: 1. first manifestation, remission and relapse of the disease depend on intake and a non-intake of water containing copper, respectively. 2. hypercupric state of the patients (i.e. pathological high concentrations of the non-ceruloplasmin-bound copper in serum and/or elevated copper levels in urine) 3. signs of systemic copper intoxication in the same patient 4. signs of systemic copper intoxication or hypercupric states in members of the patient s family or in his neighbourhood (non-relatives) - We found that the disease can even be caused by copper concentrations below the allowed concentration given by the German Guidelines for Drinking Water (Trinkwasserverordnung). - The data prove that copper in drinking water can cause gastrointestinal diseases and not only the better known systemic diseases (i.e. copper induced liver cirrhosis). Copper poisoning must be considered as a possible cause of chronic gastrointestinal diseases in those countries in which copper plumbing is common.

Adolescent↗
PubMed1999

Chronic poisoning by copper in tap water: II. Copper intoxications with predominantly systemic symptoms.

Copper can induce acute and chronic intoxications in humans. Copper in tap water has caused a series of severe systemic diseases in Germany in recent years (chronic copper poisoning, CCuP). From the clinical point of view it has been difficult to establish the diagnosis on the basis of clinical and laboratory methods. In a retrospective study, we therefore looked for essential clinical signs as well as laboratory findings which might be typical and essential for the diagnosis of CCuP. - We observed that in patients with severe systemic CCuP not only the liver but also several other organs have been the target of copper. As a proof copper overload has been measured. The latter results are presented here. - During or shortly after exposure "free" serum copper (= non-ceruloplasmin-bound copper) was significantly elevated in all patients (range 5.1 to 47.1 micromol/l, or 25.7 to 56.2 % of total serum copper). The normal upper limits in infants according to Salmenperä (8) are: 0.3 micromol/l, or 1.6 % of total serum copper. - Total serum copper was elevated in 14/16 patients: 13.7 to 30.1 micromol/l in sick infants (normal upper level: 12.6 micromol/l), and 17.0 to 27.2 in sick children (normal upper level for children and adults: 21.4 micromol/l). - Urine copper excretion was found elevated in 9/10 patients, with a range of 11 to 456 microg/dl (normal upper level in adults: 15 microg/dl). - Our results show that patients with systemic CCuP are in a "hypercupric" state. The data thus firstly prove that indeed the putative agent copper is found in excess in the patients and secondly show that the estimation of "free" copper in serum and the measurement of copper in urine are reliable diagnostic methods. Elevation of total serum copper (even though not specific) can give a first hint to the diagnosis. - The hypercupric state of systemic CCuP can be differentiated from that of Wilson's disease by (1) normal levels of ceruloplasmin and (2) the observation that values for free copper in serum or urinary copper normalize in an environment without copper in tap water, for instance in a hospital.

Adult↗
PubMed1999

Determination of idarubicin and idarubicinol in rat plasma using reversed-phase high-performance liquid chromatography and fluorescence detection.

A reversed-phase high-performance liquid chromatographic method is described for the simultaneous determination of idarubicin and idarubicinol in rat plasma. Blood samples were analyzed from 16 rats which had received an intravascular dose of 2.25 mg kg(-1) idarubicin. After deproteinization with acetonitrile, the separation was performed with a LiChrospher 100 RP-18 column (5 microm), using fluorescence detection (excitation: 485 nm/emission: 542 nm). The mean recovery was 95.6% for idarubicin and 90.7% for idarubicinol, respectively. The detection limit was 0.25 ng ml(-1) using an injection volume of 50 microl. Daily relative standard deviation (RSD) was 3.2% (10 ng idarubicin/ml, n=10) and 4.4% (10 ng idarubicinol/ml, n=10).

Animals↗
PubMed1999

[Incidence of immunogenic hyperthyroidism after radioiodine therapy of focal thyroid gland autonomy. Results of a multicenter study].

BACKGROUND: There are case reports in the literature that patients occasionally develop immunogenic hyperthyroidism 2 to 14 months following iodine-131-therapy of focal, non-immunogenic, autonomous thyroid nodules with a prevalence between 0.05 and 2.5%. Purpose of this multicenter evaluation was to assess the appearance of this phenomenon in a larger patient population. PATIENTS AND METHODS: So far 2867 patients out of 4 university hospitals are included in our study focusing on the appearance of pathologically elevated levels of thyrotropin-receptor-antibodies (TRAb) combined with hyperthyroidism following iodine-therapy. Records of the patients were screened for pre- and post-therapeutic biochemical tests, scintigraphic uptake patterns and ultrasound findings of the thyroid. RESULTS: Nineteen of 2867 patients with pretherapeutically scintigraphic "hot nodules" developed recurrent hyperthyroidism suggestive for immunogenic genesis 2 to 12 months following iodine-131-therapy (elevated TRAb-levels, homogeneous uptake in Tc-99m-pertechnetate scans). Pretherapeutically, 9 of these patients presented with a strictly focal scintigraphic uptake-pattern, 10 cases with a mixed disseminated-focal pattern. Because of missing pretherapeutic TRAb-tests in 8/9 patients presenting with a strictly focal scintigraphic uptake pattern, postradiogenic immunogenic hyperthyroidism could be reliably assessed in 1 case only. CONCLUSION: One could speculate that iodine-131-therapy may stimulate immunogenic mechanisms finally leading to immunogenic hyperthyroidism. Posttherapeutically observed hyperthyroidism following iodine-treatment might be based on an exacerbation of a preexisting--clinically not relevant/detectable--immunothyropathia. Also pretherapeutic TRAb-negative immunogenic hyperthyroidism could not be definitely excluded. Our multicenter data collected in a large patient population show similar results to the case reports of immunogenic hyperthyroidism following iodine-131-treatment in smaller populations. Therfore, the occurrence of this phenomenon plays a minor role regarding to its prevalence. Therapeutical consequences in treatment of functional thyroid autonomy are not recommended.

Adult↗
PubMed1999

Pharmacokinetics in organs and the intact body: model validation and reduction.

Physiological pharmacokinetic models are based on the structure of the circulatory system reflecting the convective transport of drug by blood flow to the various organs and tissues. Distribution kinetics at the organ level is mostly simplified as transfer between well-stirred compartments neglecting a priori the effects of intravascular dispersion and diffusion within tissue parenchyma. Recirculatory models based on residence time theory overcome these structural limitations since they allow in a most general way the decomposition of the body into its natural subsystems. Because of the unidentifiability of the global multi-organ model on the basis of plasma concentration-time curves the following methods/experimental designs will be discussed which provide quantitative information regarding the subsystems under in vivo conditions: (i) determination of tissue concentration-time profiles (destructive sampling), (ii) estimation of the organ transit time density from input/output profiles and (iii) application of a recirculatory model with reduced complexity to clinical pharmacokinetic data.

Animals↗
PubMed1999

Pharmacokinetic curve fitting using numerical inverse Laplace transformation.

The combination of the nonlinear regression program ADAPT II with Talbot's method of numerical Laplace transformation, that allows parameter estimation when the model function is given only in the Laplace domain, is described and successfully applied to pharmacokinetic problems. The accuracy and precision of the method has been found satisfactory; its performance is comparable to that achieved in parameter estimation based on functions defined in the time domain.

Algorithms↗
PubMed1999

Comparison of the angiojet rheolytic catheter to surgical thrombectomy for the treatment of thrombosed hemodialysis grafts. Peripheral AngioJet Clinical Trial.

PURPOSE: To compare the clinical effectiveness of the AngioJet F105 rheolytic catheter to that of surgical thrombectomy for the treatment of thrombosed hemodialysis grafts. MATERIALS AND METHODS: This was a multicenter, prospective, randomized trial comparing technical success, primary patency, and complication rates. A total of 153 patients were enrolled: 82 patients in the AngioJet group and 71 patients in the surgical thrombectomy group. Patient follow-up was performed 24-48 hours, 1 month, and 6 months after the procedures. RESULTS: Technical success, as defined by the patient's ability to undergo hemodialysis treatment, was 73.2% for the AngioJet group and 78.8% for the surgical thrombectomy group (P = .41). The primary patency rates of the AngioJet group were 32%, 21%, and 15% at 1, 2, and 3 months, respectively. The primary patency rates for the surgical group were 41%, 32%, and 26% at 1, 2, and 3 months, respectively. This difference approached statistical significance (P = .053). The groups had similar complication rates-14.6% in the AngioJet group and 14.1% in the surgery group-although the surgery group had more major complications (11.3%). In the AngioJet group, there was a transient increase in plasma-free hemoglobin, which normalized within 24-48 hours. CONCLUSIONS: The AngioJet F105 catheter provides similar clinical results when compared to surgical thrombectomy for the treatment of thrombosed hemodialysis grafts. The difference in patency rates between these two techniques approached statistical significance. In addition, results of both thrombectomy methods were inferior to those suggested by the Dialysis Outcomes Quality Initiative guidelines.

Adult↗
PubMed1999

Does the dose-solubility ratio affect the mean dissolution time of drugs?

PURPOSE: To present a new model for describing drug dissolution. On the basis of the new model to characterize the dissolution profile by the distribution function of the random dissolution time of a drug molecule, which generalizes the classical first order model. METHODS: Instead of assuming a constant fractional dissolution rate, as in the classical model, it is considered that the fractional dissolution rate is a decreasing function of the dissolved amount controlled by the dose-solubility ratio. The differential equation derived from this assumption is solved and the distribution measures (half-dissolution time, mean dissolution time, relative dispersion of the dissolution time, dissolution time density, and fractional dissolution rate) are calculated. Finally, instead of monotonically decreasing the fractional dissolution rate, a generalization resulting in zero dissolution rate at time origin is introduced. RESULTS: The behavior of the model is divided into two regions defined by q, the ratio of the dose to the solubility level: q < 1 (complete dissolution of the dose, dissolution time) and q > 1 (saturation of the solution, saturation time). The singular case q = 1 is also treated and in this situation the mean as well as the relative dispersion of the dissolution time increase to infinity. The model was successfully fitted to data (1). CONCLUSIONS: This empirical model is descriptive without detailed physical reasoning behind its derivation. According to the model, the mean dissolution time is affected by the dose-solubility ratio. Although this prediction appears to be in accordance with preliminary application, further validation based on more suitable experimental data is required.

Capsules↗
PubMed1999

The anomalous pharmacokinetics of amiodarone explained by nonexponential tissue trapping.

Conventional pharmacokinetic (PK) concepts fail to describe the long-term pharmacokinetics of the extremely cationic amphiphilic drug amiodarone. A nonclassical model based on the phenomenon of trapping at tissue binding sites with very long release times is presented, which implies that a volume of distribution and a steady-state level cannot be defined. In agreement with clinical PK data available in the literature, the model well describes not only single-dose disposition curves but also the persistently increasing plasma concentration-time curve during long-term treatment (up to 5 years) and the washout curve following cessation of therapy. The novel aspect is a long-tailed tissue residence time distribution which is incorporated into a recirculatory model leaving the initial distribution process and the clearance concept unchanged. The underlying theoretical approach, which is known as "strange or anomalous" kinetics in physical sciences, and the fractal scaling property of the model may enhance our understanding of the PK of extremely hydrophobic xenobiotics.

Amiodarone↗
PubMed1999

Cellular pharmacokinetics: effects of cytoplasmic diffusion and binding on organ transit time distribution.

Distribution between well-stirred compartments is the classical paradigm in pharmacokinetics. Also in capillary-issue exchange modeling a barrier-limited approach is mostly adopted. As a consequence of tissue binding, however, drug distribution cannot be regarded as instantaneous even at the cellular level and the distribution process consists of at least two components: transmembrane exchange and cytoplasmic transport. Two concepts have been proposed for the cytoplasmic distribution process of hydrophobic or amphipathic molecules, (i) slowing of diffusion due to instantaneous binding to immobile cellular structures and (ii) slow binding after instantaneous distribution throughout the cytosol. The purpose of this study was to develop a general approach for comparing both models using a stochastic model of intra- and extravascular drug distribution. Criteria for model discrimination are developed using the first three central moments (mean, variance, and skewness) of the cellular residence time and organ transit time distribution, respectively. After matching the models for the relative dispersion the remaining differences in relative skewness are predicted, discussing the relative roles of membrane permeability, cellular binding and cytoplasmic transport. It is shown under which conditions the models are indistinguishable on the basis of venous organ outflow concentration-time curves. The relative dispersion of cellular residence times is introduced as a model-independent measure of cytoplasmic equilibration kinetics, which indicates whether diffusion through the cytoplasm is rate limiting. If differences in outflow curve shapes (their relative skewness) cannot be detected, independent information on binding and/or diffusion kinetics is necessary to avoid model misspecification. The method is applied to previously published hepatic outflow data of enalaprilat, triiodothyronine, and diclofenac. It provides a general framework for the modeling of cellular pharmacokinetics.

Animals↗
PubMed1999

Nutritional status and growth after bone marrow transplantation (BMT) during childhood: EBMT Late-Effects Working Party retrospective data. European Group for Blood and Marrow Transplantation.

The European Group for Blood and Marrow Transplantation (EBMT) Late-Effects Working Party collected data on patients who survived more than 5 years after BMT. Height at transplant and at the latest follow-up examination were evaluated in 79/258 subjects who were below the age of 15 at BMT. A significant decrease in height-standard deviation score (SDS) was observed in leukemic children conditioned with total body irradiation (TBI) and in those who received both cranial irradiation and TBI. The majority of these patients, however, received single-dose TBI (28/41). A significant decrease in height-SDS was also seen in children who received thoraco-abdominal irradiation suggesting that the deleterious effect of irradiation on growth after BMT is not entirely due to injury to cranial neuroendocrine structures, but also probably due to damage to bone epiphyses, thyroid and gonads. A non-significant decrease in height was observed in children transplanted using chemotherapy alone. Nutritional status, expressed as body-mass index (BMI), was found unchanged in the adult group (n = 158). A significant increase in BMI was observed in the younger patients (n = 88), which parallels the normal increase in BMI observed during childhood. This suggests that on long-term analysis, a good nutritional status is maintained in patients undergoing BMT at any age.

Adolescent↗