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Biomedical subjects

A Lamprecht

Publications and source records attributed to A Lamprecht.

At least 19 recordsLinked to original sources
PubMed2005

T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma.

The three chromosomal translocations t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32) are associated with MALT lymphoma. In a case of MALT lymphoma of the thyroid, we observed t(3;14)(p14.1;q32) by cytogenetic analysis. Fluorescence in situ hybridization studies showed that the immunoglobulin heavy chain locus (IGH) was rearranged on chromosome 14. Long-distance inverse polymerase chain reaction identified FOXP1 as the partner gene on chromosome 3. To determine the frequency of the t(3;14)(p14.1;q32), two fluorescence in situ hybridization assays were established to screen 91 MALT lymphomas, all of which were negative for the above-mentioned three translocations, and eight splenic and six nodal marginal zone lymphomas. Overall, nine MALT lymphomas (10%) harbored t(3;14)(p14.1;q32) comprising tumors of the thyroid (three of six), ocular adnexa (four of 20), and skin (two of 20), whereas those of the stomach (n = 20), salivary gland (n = 20), and lung (n = 5) were negative as well as the splenic and nodal marginal zone lymphomas. Most t(3;14)(p14.1;q32) + MALT lymphomas harbored additional genetic abnormalities, such as trisomy 3. Further studies revealed that the three known translocations and t(3;14)(p14.1;q32) are mutually exclusive. Real-time quantitative reverse transcriptase polymerase chain reaction showed upregulation of FOXP1 in cases with t(3;14)(p14.1;q32) or trisomy 3. This study identifies FOXP1 as a new translocation partner of IGH in a site-dependent subset of MALT lymphomas.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites.

Although several recurrent genetic aberrations are known to occur in MALT lymphoma, no comprehensive study on the most prevalent MALT lymphoma-associated genetic aberrations is available. We therefore screened 252 primary MALT lymphomas for translocations t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32), and trisomies 3 and 18. The above-listed translocations occurred mutually exclusively and were detected overall in 13.5, 10.8, and 1.6% of the cases; trisomy 3 and/or 18 occurred in 42.1%. The frequency at which the translocations occurred varied markedly with the primary site of disease. The t(11;18)(q21;q21) was mainly detected in pulmonary and gastric tumors, whereas the t(14;18)(q32;q21) was most commonly found in lesions of the ocular adnexa/orbit, skin, and salivary glands. Trisomies 3 and 18 each occurred most frequently in intestinal and salivary gland MALT lymphomas. Our results demonstrate that the three translocations and trisomies 3 and 18 occur at markedly variable frequencies in MALT lymphoma of different sites.

Chromosome Aberrations↗
PubMed2003

Non-degradable microparticles containing a hydrophilic and/or a lipophilic drug: preparation, characterization and drug release modeling.

Non-degradable microparticles based on ammonio methacrylate copolymers (Eudragit RS:RL 4:1 blends) containing the hydrophilic drug propranolol HCl and/or the lipophilic drug nifedipine were prepared with an oil-in-water (O/W) and a water-in-oil-in-water (W/O/W) solvent evaporation technique. Both drugs were successfully incorporated separately as well as simultaneously. In all cases, the resulting release rate(s) of the drug(s) was/were found to be controlled over periods of at least 8 h. To elucidate the underlying mass transport mechanisms, the microparticles were thoroughly characterized by X-ray powder diffractometry, differential scanning calorimetry, particle size analysis, and determination of the actual drug loading(s). Analytical solutions of Fick's second law of diffusion considering non-steady state conditions were used to describe the release of propranolol HCl. Interestingly, the resistance for drug release within the unstirred liquid boundary layers on the surfaces of the microparticles was found to be negligible compared to the diffusional resistance within the polymeric devices. Importantly, the mathematical theories could be used to normalize the experimentally determined in vitro drug release with respect to the microparticle size. Thus, the effect of the type of preparation method (O/W vs. W/O/W) and device composition (polymer blend plus one drug only vs. polymer blend plus drug combination) on the diffusional resistance within the microparticles could be studied. In addition, further insight into the occurring mass transport processes was gained. For example, the time-dependent evolution of the drug concentration profiles within the microparticles upon exposure to the release medium could be calculated. An interesting practical application of the mathematical theories is the possibility to predict the effect of different formulation parameters on the resulting drug release patterns, e.g. the effect of the microparticle size.

Chemistry, Pharmaceutical↗
PubMed2001

Design of rolipram-loaded nanoparticles: comparison of two preparation methods.

The aim of the present work was to investigate the preparation of nanoparticles as a potential drug carrier and targeting system for the treatment of inflammatory bowel disease. Rolipram was chosen as the model drug to be incorporated within nanoparticles. Pressure homogenization-emulsification (PHE) with a microfluidizer or a modified spontaneous emulsification solvent diffusion method (SESD) were used in order to select the most appropriate preparation method. Poly(epsilon-caprolactone) has been used for all preparations. The drug loading has been optimized by varying the concentration of the drug and polymer in the organic phase, the surfactants (polyvinyl alcohol, sodium cholate) as well as the volume of the external aqueous phase. The rolipram encapsulation efficiency was high (>85%) with the PHE method in all cases, whereas with the SESD method encapsulation efficiencies were lower (<40%) when lower surfactant concentrations and reduced volume of aqueous phase were used. Release profiles were characterized by a substantial initial burst release with the PHE method (25-35%) as well as with the SESD method (70-90%). A more controlled release was obtained after 2 days of dissolution with the PHE method (70-90%), no further significant drug release was observed with the SESD method.

Algorithms↗
PubMed2001

Study of beta-lactoglobulin/acacia gum complex coacervation by diffusing-wave spectroscopy and confocal scanning laser microscopy.

Complex coacervation has been investigated on mixtures of beta-lactoglobulin (beta-lg) and acacia gum (AG) at pH 4.2 where these two macromolecules interact electrostatically. Changes in beta-lg/AG complex coacervation induced by the presence of beta-lg aggregates were considered. The nature and structure of particles resulting from complex coacervation were determined by using confocal scanning laser microscopy (CSLM). CSLM revealed fundamental differences in the structure of each of the studied dispersions (at 1 wt.% total concentration). Spherical vesicular coacervates and precipitates (based on beta-lg aggregates) were the hallmark of BLG/AG dispersions (beta-lg dispersion containing insoluble aggregates). Only coacervates were visible in AF-BLG/AG dispersions (beta-lg dispersion free of insoluble aggregates). The latter were characterised by the presence of large foam-like coacervates induced by partial coalescence of single coacervates, especially at the 2:1 protein to polysaccharide (Pr:Ps) ratio. Diffusing wave spectroscopy (DWS) was used to study the stability of dispersions as a function of time. Depending on the Pr:Ps ratio and the presence of beta-lg aggregates, the intensity correlation function (g(2)(t)) shifted to lower correlation times rapidly after mixing of both macromolecules. This revealed the formation of a large number of small particles, characterised by faster Brownian motion. At 1 and 5 wt.% total concentration, the 8:1 Pr:Ps ratio exhibited a rapid decrease of the backscattered intensity in time, both for BLG/AG and AF-BLG/AG mixtures, revealing rapid sedimentation/coalescence of particles. This precluded the achievement of a stable correlation function. For the 2:1 Pr:Ps ratio, mixtures exhibited both coalescence and sedimentation phenomena as confirmed by shifts in the g(2)(t) towards larger correlation times and the decrease of the initial value of g(2)(t) with time. Mixtures obtained for the 1:1 Pr:Ps ratio were characterised by small variations in the DWS signal, emphasising the stability of produced particles. The increase of the total biopolymer concentration reduced the effect of both Pr:Ps ratio and presence of protein aggregates. From CSLM and DWS observations, possible differences in the complex coacervation mechanism in both types of mixtures were highlighted. The use of protein aggregates to control complex coacervation was underlined.

Journal Article↗
PubMed2001

Size-dependent bioadhesion of micro- and nanoparticulate carriers to the inflamed colonic mucosa.

PURPOSE: The size-dependent deposition of microparticles and nanoparticles after oral administration to rats using an experimental model colitis was examined. Local delivery of an entrapped drug could reduce side effects and would be a distinct improvement compared with existing colon delivery devices. METHODS: Ulcerative colitis was induced in Lewis rats with trinitrobenzenesulfonic acid. Fluorescent polystyrene particles with a size of 0.1, 1, or 10 microm were administered for 3 days. The animals then were sacrificed and their guts resected. Particle distribution in the colon was imaged by confocal laser scanning microscopy and quantified by fluorescence spectrophotometry. RESULTS: In the inflamed tissue, an increased adherence of particles was observed at the thicker mucus layer and in the ulcerated regions. A size dependency of the deposition was found, and an increased number of attached particles to the colon was determined compared with the control group. For 10-micorm particles, only fair deposition was observed (control group: 1.4 +/- 0.6%; colitis: 5.2 +/- 3.8% of administered particle mass). One-micrometer particles showed higher binding (control group: 2.0 +/- 0.8%; colitis: 9.1 +/- 4.2%). Highest binding was found for 0.1-microm particles (control group: 2.2 +/- 1.6%; colitis: 14.5 +/- 6.3%). The ratio of colitis/control deposition increased with smaller particle sizes. CONCLUSIONS: The use of submicron-sized carriers holds promise for the targeted delivery of drugs to the inflamed colonic mucosal areas in inflammatory bowel disease.

Adhesives↗
PubMed2001

Biodegradable nanoparticles for targeted drug delivery in treatment of inflammatory bowel disease.

The use of nanoparticles for targeted oral drug delivery to the inflamed gut tissue in inflammatory bowel disease was examined. Such a strategy of local drug delivery would be a distinct improvement compared with existing colon delivery devices for this disease. An experimental colitis was induced by trinitrobenzenesulfonic acid to male Wistar rats. Rolipram, an anti-inflammatory model drug, was incorporated within poly(lactic-coglycolic acid) nanoparticles, which were administered once a day orally for five consecutive days. A clinical activity score and myeloperoxidase activity were determined to assess the inflammation, whereas an adverse effect index reflected the remaining neurotropic effect of rolipram resulting from its systemic absorption. All nanoparticle formulations proved to be as efficient as the drug in solution in mitigating the experimental colitis. The clinical activity score and myeloperoxidase activity decreased significantly after the oral administration of rolipram nanoparticles or solution. During the next 5 days when animals were kept without drug treatment the drug solution group displayed a strong relapse, whereas the nanoparticle groups continued to show reduced inflammation levels. The rolipram solution group had a high adverse effect index, whereas the rolipram nanoparticle groups proved their potential to retain the drug from systemic absorption as evidenced by a significantly reduced index. This new delivery system enabled the drug to accumulate in the inflamed tissue with higher efficiency than when given as solution. The nanoparticle deposition in the inflamed tissue should be given particular consideration in the design of new carrier systems for the treatment of inflammatory bowel disease.

Animals↗
PubMed2000

Biodegradable microparticles as a two-drug controlled release formulation: a potential treatment of inflammatory bowel disease.

A multiple unit dosage form for oral delivery based on the microencapsulation of anti-inflammatory drugs using different biodegradable polymers, poly(epsilon-caprolactone), polylactic acid and poly(lactic-co-glycolic acid), prepared either by the water-in-oil-in-water (w/o/w) or the solid-in-oil-in-water (s/o/w) solvent evaporation method was developed. Microparticles were characterized for their size, morphology, encapsulation efficiency and drug release. The physical state of drugs and polymers was determined by differential scanning calorimetry (DSC), imaging of the particles was performed by scanning electron microscopy and confocal laser scanning microscopy. Sulfasalazine and betamethasone used for the treatment of inflammatory bowel disease, were chosen as model drugs. The microparticles were spherical with diameters in the range of 91 to 258 microm by the w/o/w-method, and in the range of 102 to 277 microm by the s/o/w-method. The encapsulation efficiency (EE) varied between 11 and 16% for sulfasalazine and 50 and 67% for betamethasone with the w/o/w-method, and between 73 and 79% for sulfasalazine and 60 and 70% for betamethasone with the s/o/w-method. DSC showed no interaction between polymers and drugs, while the drugs were dispersed in the polymer. In vitro release studies showed a controlled release of sulfasalazine and betamethasone from microparticles prepared by the s/o/w-method; a pronounced burst release of sulfasalazine was observed from microparticles prepared by the w/o/w-method.

Betamethasone↗
PubMed2000

Structural analysis of microparticles by confocal laser scanning microscopy.

This study demonstrates the potential of confocal laser scanning microscopy (CLSM) as a characterization tool for different types of microparticles. Microparticles were prepared by various methods including complex coacervation, spray drying, double emulsion solvent evaporation technique, and ionotropic gelation. Protein drugs and particle wall polymers were covalently labeled with a fluorescent marker prior to particle preparation, while low molecular weight drugs were labeled by mixing with a fluorescent marker of similar solubility properties. As was demonstrated in several examples, CLSM allowed visualization of the polymeric particle wall composition and detection of heterogeneous polymer distribution or changes in polymer matrix composition under the influence of the drug. Furthermore, CLSM provides a method for three-dimensional reconstruction and image analysis of the microparticles by imaging several coplanar sections throughout the object. In conclusion, CLSM allows the inspection of internal particle structures without prior sample destruction. It can be used to localize the encapsulated compounds and to detect special structural details of the particle wall composition.

Drug Compounding↗
PubMed2000

The preparation and evaluation of poly(epsilon-caprolactone) microparticles containing both a lipophilic and a hydrophilic drug.

An original dosage form for oral delivery based on the encapsulation of both, lipophilic and hydrophilic drugs, in poly(epsilon-caprolactone) (PCL) microparticles prepared either by the oil-in-water (o/w) or the water-in-oil-in-water (w/o/w) solvent evaporation method was developed. Microparticles were characterized in terms of morphology, size, encapsulation efficiency and drug release. The physical state of the drugs and the polymer was determined by scanning electron microscopy (SEM), X-ray powder diffractometry, and differential scanning calorimetry (DSC). Nifedipine (calcium antagonist) and propranolol HCl (beta-blocker), used for the treatment of hypertension, were chosen as lipophilic and hydrophilic drugs. The microparticles were spherical with diameters in the range of 191-351 microm by the o/w-method, and in the range of 302-477 microm by the w/o/w-method. The encapsulation efficiency (EE) was 91% for nifedipine and 37% for propranolol HCl with the o/w-method, and 83% for nifedipine and 57% for propranolol HCl with the w/o/w-method. DSC and X-ray diffraction studies showed that PCL maintained its semi-crystalline structure, while the drugs were either dispersed or dissolved in the polymer. In vitro release studies revealed a controlled release of nifedipine and propranolol HCl from microparticles prepared by the o/w-method; a burst release of propranolol HCl was observed from microparticles prepared by the w/o/w-method. In conclusion, microparticles containing both a hydrophilic and a lipophilic drug were successfully prepared.

Adrenergic beta-Antagonists↗
PubMed2000

Influences of process parameters on nanoparticle preparation performed by a double emulsion pressure homogenization technique.

The preparation of nanoparticles (NP) as an improved colloidal carrier system for proteins was investigated. Bovine serum albumin (BSA) was used as model drug. Owing to the high solubility of the protein in water, the double emulsion technique has been chosen as one of the most appropriate method. In order to both reaching submicron size as well as increasing the grade of monodispersity compared to previous preparation techniques, a microfluidizer as homogenization device was used. All experiments were performed using two biodegradable polymers, poly[D,L-lactic-co-glycolic acid] 50/50 (PLGA) and poly[epsilon-caprolactone] (PCL). The homogenization procedure has been optimized with regard to particle size and monodispersity by studying the influence of the homogenization time as well as the amount of polymer and surfactant in the external aqueous phase. The drug loading has been improved by varying the concentration of the protein in the inner aqueous phase. By increasing the protein concentration in the inner aqueous phase the polydispersity was slightly higher, while the particle size was not influenced significantly. The BSA encapsulation efficiency decreased with higher protein concentration in the inner aqueous phase. All release profiles were characterized by a initial burst effect, a higher release rate was obtained after 4 weeks for PLGA NP (60%) compared with PCL NP (47%).

Animals↗
PubMed2000

Visualization and quantification of polymer distribution in microcapsules by confocal laser scanning microscopy (CLSM).

Confocal laser scanning microscopy (CLSM) was employed in order to characterize microcapsules. Microcapsules were prepared by complex coacervation: gelatin and arabic gum were labelled with fluorescent markers. In the capsule wall a homogeneous distribution for both gelatin and arabic gum throughout the capsule wall was depicted. By the use of CLSM and a computational image analysis the quantification of the labelled polymer in the wall material was possible. Adding fluorescently labelled casein as a macromolecular model compound to the coacervation process, a gradiental distribution in the wall material was observed with highest concentration of casein at the oil-wall interface. The influence of casein concentration on its deposition behaviour in the capsule wall was imaged successfully and thereafter quantified by computational image analysis.

Capsules↗
PubMed2000

Characterization of microcapsules by confocal laser scanning microscopy: structure, capsule wall composition and encapsulation rate.

The potential of confocal laser scanning microscope (CLSM) has been evaluated for characterizing microcapsules. The aim was to visualize the polymer distribution within the particle wall, and to localize and to quantify the encapsulated oil phase. Microcapsules were prepared by complex coacervation: the oil phase, gelatine, and arabic gum were labelled with fluorescent markers. For all compounds it was proved that fluorescence labelling did not alter physico-chemical properties critical to the encapsulation process. Labelling of the inner oil phase allowed us to identify and to localize, three-dimensionally, the encapsulated compound. A homogeneous distribution for both gelatine and arabic gum throughout the capsule wall was observed. The addition of fluorescently labelled casein as a macromolecular model compound to the coacervate resulted in an inhomogeneous distribution of casein within the wall material, the highest concentration of casein was found at the oil-wall interface. To determine the encapsulation rate, CLSM pictures of the microcapsule samples were acquired using different fluorescence labels for the microcapsule wall polymers and the incorporated oil phase, respectively. By applying computational image analysis, the volumes of the different phases were calculated. Comparing the results of non-destructive image analysis with those obtained by degradation, extraction and chemical analysis, a linear relation was found with correlation coefficients better than 0.980.

Capsules↗
PubMed1999

Biodegradable monodispersed nanoparticles prepared by pressure homogenization-emulsification.

The aim of the present work was to investigate the preparation of nanoparticles (NP) as potential drug carriers for proteins. The hydrophilic protein bovine serum albumin (BSA) was chosen as the model drug to be incorporated within NP. Owing to the high solubility of the protein in water, the double emulsion technique has been chosen as one of the most appropriate method. In order to reach submicron size we used a microfluidizer as a homogenization device with a view to obtaining NP with a very high grade of monodispersity. Two different biodegradable polymers, poly[D, L-lactic-co-glycolic acid] 50/50 (PLGA) and poly[epsilon-caprolactone] (PCL) has been used for the preparation of the NP. The drug loading has been optimized by varying the concentration of the protein in the inner aqueous phase, the polymer in the organic phase, the surfactant in the external aqueous phase, as well as the volume of the external aqueous phase. The BSA encapsulation efficiency was high (>80%) and release profiles were characterized by a substantial initial burst release for both PLGA and PCL NP. A higher release was obtained at the end of the dissolution study for PLGA NP (92%) compared with PCL NP (72%).

Biocompatible Materials↗
PubMed1999

Aberrant esophageal HLA-DR expression in a high percentage of patients with Crohn's disease.

Esophageal histology is not well studied in patients with Crohn's disease (CD). We, therefore, analyzed the histologic and immunohistologic appearance of esophageal mucosa in CD. Biopsy specimens taken from the esophagus of 57 consecutive patients with known CD of the large and/or small bowel, of 200 Crohn's-free controls, of 15 cases with ulcerative colitis, and of 5 cases with viral esophagitis were evaluated. In controls, most patients had either HLA-DR negative esophageal epithelium or showed focal or diffuse basal staining. HLA-DR expression of all epithelial layers (transepithelial staining) was observed in only four (2%) control subjects, in one case with herpes esophagitis, but not in patients with ulcerative colitis. In contrast, transepithelial HLA-DR expression was found in 19 (33%) patients with CD (p < 0.0001). In CD patients, it was associated with a significantly increased epithelial content in T-cells (CD3+, TIA-1+, granzyme B+), B-cells (CD79a+), natural killer cells (CD57+), and macrophages (CD68+). There was no correlation with either histological findings elsewhere in the upper gastrointestinal tract or with laboratory findings, symptoms, CDAI, or medication. Transepithelial esophageal HLA-DR expression is common in CD. Immunohistochemistry may prove useful in supporting the histologic diagnosis of CD in staging procedures, for initial diagnosis as well as in doubtful cases.

Adolescent↗
PubMed1998

Approaches to the genetics of cardiovascular disease through genetic field work.

Successful molecular genetic studies of complex disease require exact, careful phenotypization, which is more difficult than that performed for monogenic diseases. We have developed a family-oriented field working approach, which relies on index patients, their primary care physicians, and a minimum number of field working staff. The patients are responsible for recruiting their family members. Packets containing an explanatory pamphlet, an informed consent statement, a questionnaire, and blood cuvettes are provided. Data are transferred from questionnaire and from the laboratory into a computer program that facilitates construction of the family tree. We have applied this genetic field working approach primarily to patients with lipid disorders. Coupling results from genetic field working with modern DNA diagnostic tests such as the oligonucleotide ligation assay, has enabled us to effectively identify patients with familial hypercholesterolemia in the German population. We are now extending genetic field working to hypertension. Hypertension is much more difficult to study, because the phenotype is more difficult to discern and document. Both complex diseases have the disadvantage that the parents of the index patients are likely to already be dead. Nevertheless, we concentrate on the recruitment of large pedigrees, sibling pairs with parents whenever possible, and trios consisting of index patient and both parents or index patient, parent and sibling. With these constellations we can conduct association studies, linkage analysis, and novel combinations of both approaches.

Automation↗
PubMed1996

The ATP-binding cassette multidrug transporter Snq2 of Saccharomyces cerevisiae: a novel target for the transcription factors Pdr1 and Pdr3.

Pleiotropic drug resistance (PDR) in the yeast Saccharomyces cerevisiae can arise from overexpression of ATP-binding cassette (ABC) efflux pumps such as Pdr5 and Snq2. Mutations in the transcription factor genes PDR1 and PDR3 are also associated with PDR. We show here that a pdr1-3 mutant exhibits a PDR phenotype, including elevated resistance to the mutagen 4-nitroquinoline-N-oxide, a known substrate for Snq2 but not for Pdr5. Northern analysis and immunoblotting demonstrated that the SNQ2 gene is 10-fold overexpressed in a pdr1-3 gain-of-function mutant strain, whereas Snq2 expression is severely reduced in a delta pdr1 deletion strain, and almost abolished in a delta pdr1 delta pdr3 double disruptant when compared to the PDR1 strain. However, expression of the Ste6 a-factor pheromone transporter, another yeast ABC transporter not associated with PDR, is unaffected in pdr1-3 mutant cells and in strains carrying delta pdr1, delta pdr3, or delta pdr1 delta pdr3 deletions. Finally, DNA footprint analysis revealed that the SNQ2 promoter contains three binding sites for Pdr3. Our results identify SNQ2 as a novel target for both Pdr1 and Pdr3, and demonstrate that the PDR phenotype of a pdr1-3 mutant strain results from overexpression of more than one ABC drug-efflux pump.

4-Nitroquinoline-1-oxide↗