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Biomedical subjects

N Weber

Publications and source records attributed to N Weber.

At least 19 recordsLinked to original sources
PubMed2005

Copolymeric polythioesters by lipase-catalyzed thioesterification and transthioesterification of alpha,omega-alkanedithiols.

Linear copolymeric polythioesters [PTE; poly(alpha,omega-alkanedioic acid-co-alpha,omega-alkanedithiols)] were formed in good yield (approximately 69%) by thioesterification of 1,12-dodecanedioic acid with 1,6-hexanedithiol and 1,8-octanedithiol, respectively, catalyzed by immobilized lipase from Rhizomucor miehei (Lipozyme RM IM) in vacuo without a solvent. Similarly, transthioesterification (thiolysis) of diethyl 1,12-dodecanedioate with 1,6-hexanedithiol led to the formation of approximately 66% PTE. Poly (1,12-dodecanedioic acid-co-1,6-hexanedithiol) and poly (1,12-dodecanedioic acid-co-1,8-octanedithiol) were extracted from the reaction mixture using methyl-t-butylether, precipitated at -20 degrees C and the precipitates extracted with boiling i-hexane to yield two fractions of PTE. The i-hexane-insoluble fraction of poly (1,12-dodecanedioic acid-co-1,6-hexanedithiol) shows an average molecular mass (Mw) of 1,212 Da, corresponding to a molecular weight range of up to 13,200 Da and a degree of polymerization of up to 38 monomer units. The i-hexane-insoluble fraction of poly (1,12-dodecanedioic acid-co-1,8-octanedithiol) shows a Mw of 2,360 Da, corresponding to a molecular weight range of up to 19,500 Da and a maximum degree of polymerization of up to 52 monomer units. The low-molecular weight (<800 Da) reaction products of thioesterification of 1,12-dodecanedioic acid with 1,6-hexanedithiol, elucidated by gas chromatography-mass spectroscopy, show the following intermediates: (1) 9,20-dioxo-1,8-dithiacycloeicosane; (2) 17,28-dioxo-1,8,9,16-tetrathiacyclooctacosane; (3) 1,12-dodecanedioic acid methyl(O)ester 6'-S-mercaptohexyl thio(S)ester; and (4) oligomeric linear thioester, formed by thioesterification of two molecules of 1,12-dodecanedioic acid with one molecule of 1,6-hexanedithiol.

Alkanes↗
PubMed2005

Characterization of the nuclear import of human MutLalpha.

DNA mismatch repair (MMR) is essential for the maintenance of replication fidelity. Its major task is to recognize mismatches as well as insertion/deletion loops of newly synthesized DNA strands. Although different players of human MMR have been identified, the regulation of essential steps of MMR is poorly understood. Because MMR is initiated in the nucleus, nuclear import might be a mechanism to regulate MMR. Nuclear targeting is accomplished by conserved signal sequences called nuclear localization signals (NLS), which represent clusters of positively charged amino acids (aa). hMLH1 contains two clusters of positively charged amino acids, which are candidate NLS sequences (aa 469-472 and 496-499), while hPMS2 contains one (aa 574-580). To study the effect of these clusters on nuclear import, NLS mutants of hMLH1 and hPMS2 were generated and expressed in 293T cells. The subcellular localization of the mutant constructs was monitored by confocal laser microscopy. We demonstrated that missense mutations of two signal sequences, one in hMLH1 and one in hPMS2, lead to impaired nuclear import, which was especially prominent for mutants of the hMLH1 residues K471 and R472; and hPMS2 residues K577 and R578.

Amino Acid Sequence↗
PubMed2005

[The ovarian hyperstimulation syndrome -- a rare differential diagnosis of a unilateral pleural effusion].

This case presentation describes a 29 year-old female who developed a severe ovarian hyperstimulation syndrome (OHSS) with ascites and a right-sided pleural effusion following in-vitro-fertilisation. A total of 4,2 l of pleural fluid was removed during 3 thoracocenteses. The symptoms as well as the fluid production ceased after 2 weeks. The OHSS is altogether a rare, but potentially life-threatening complication of in-vitro-fertilisation. Due to the well-characterized clinical setting in which the syndrome appears, there are only few differential diagnoses to consider. OHSS is likely to originate from altered capillary permeability, but its pathogenesis is not yet fully understood. Clinical symptoms usually resolve within 2 weeks of supportive therapy. In case of persistency, however, especially pulmonary embolism and infectious causes of pleural fluid production have to be excluded.

Adult↗
PubMed2005

Optimum peripheral drug deposition in patients with cystic fibrosis.

In order to identify the optimum particle size and breathing pattern for high peripheral deposition of inhaled drugs in patients with cystic fibrosis, regional deposition in these patients was studied systematically as a function of particle size, inhalation volume and flow rate. Regional deposition was assessed using the single-breath regional deposition technique in which the concentration profile of inhaled and exhaled non-radioactive, monodisperse test particles is analyzed. Using this technique particle deposition within the functional dead space volume and peripherally can be assessed. Regional deposition was measured in 12 patients with cystic fibrosis using 2, 3, 4, and 5.5 microm particles, inhalation volumes of 500, 1000, 1500, and 2000 cm(3), and inhalation flow rates of 100, 250, 500, and 750 cm(3)/sec. Peripheral deposition was highest when 2-3-microm particles were inhaled with air-flow rates of 250-500 cm(3)/sec. With these parameters peripheral deposition increased with increasing inhalation volume and reached values of about 60% of the total drug inhaled. It has been shown that high peripheral drug deposition can be achieved in patients with CF when inhalations are performed using an optimized combination of particle size and breathing pattern.

Administration, Inhalation↗
PubMed2004

Mono-thioesters and di-thioesters by lipase-catalyzed reactions of alpha,omega-alkanedithiols with palmitic acid or its methyl ester.

1- S-Mono-palmitoyl-hexanedithiol and 1- S-mono-palmitoyl-octanedithiol were prepared in high yield (80-90%) by solvent-free lipase-catalyzed thioesterification of palmitic acid with the corresponding alpha,omega-alkanedithiols in vacuo. Similarly, 1,6-di- S-palmitoyl-hexanedithiol and 1,8-di- S-palmitoyl-octanedithiol were prepared in moderate yield (50-60%) by solvent-free lipase-catalyzed thioesterification of palmitic acid with 1- S-Mono-palmitoyl-hexanedithiol and 1- S-mono-palmitoyl-octanedithiol, respectively. An immobilized lipase preparation from Rhizomucor miehei (Lipozyme RM IM) was more effective than a lipase B preparation from Candida antarctica (Novozym 435) or a lipase preparation from Thermomyces lanuginosus (Lipozyme TL IM). Lipase-catalyzed transthioesterifications of methyl palmitate with alpha,omega-alkanedithiols using the same enzymes were less effective than thioesterification for the preparation of the corresponding 1- S-mono-palmitoyl thioesters.

Ascomycota↗
PubMed2004

[Xenon - noble gas with organprotective properties].

Besides it's anaesthetic properties, xenon may induce biological effects that may protect various organs from ischaemia-reperfusion injury. Xenon is an antagonist of the NMDA-receptor and reduces the neuronal injury mediated via these receptors. In contrast to other NMDA-receptor antagonists, xenon has no neurotoxic side effects. Xenon also protects the heart in ischaemia-reperfusion situations. Xenon reduces the post-ischaemic reperfusion injury and offers cardioprotection by inducing pharmacological preconditioning. These organ protective properties of xenon might be useful in special clinical situations.

Anesthetics, Inhalation↗
PubMed2004

Characterization of a population of small macrophages in induced sputum of patients with chronic obstructive pulmonary disease and healthy volunteers.

The inflammatory process in chronic obstructive pulmonary disease (COPD) is active mainly in the airways, but little is known about the properties of the inflammatory cells in this compartment. We have studied leucocytes in induced sputum of COPD patients compared to controls in order to uncover what types of macrophages might be involved in the disease. Sputum induction was performed by inhalation of nebulized sodium chloride solution. Leucocytes were isolated and stained with specific monoclonal antibodies for analysis in flow cytometry. Flow cytometry analysis revealed that a major portion of CD14+ macrophages in COPD has lower forward scatter, i.e. they are small macrophages. While in control donors these small macrophages accounted for 6.9% of all macrophages, the percentage of these cells in COPD was 45.7%. CD14 and HLA-DR expression was high on these small sputum macrophages while the large sputum macrophages expressed only low levels of these surface molecules, both in control donors and COPD patients. Small sputum macrophages of both control donors and COPD patients showed higher levels of constitutive tumour necrosis factor (TNF) compared to the large macrophages. TNF was inducible by lipopolysaccharide (LPS) preferentially in the small sputum macrophages in the control donors but there was no further induction in COPD patients. These data show that the small sputum macrophages are a major macrophage population in COPD and that these cells exhibit features of highly active inflammatory cells and may therefore be instrumental in airway inflammation in COPD.

Adult↗
PubMed2003

[Pulmonary infiltrates with blood eosinophilia in a 62-year-old patient].

A 62-year-old woman was admitted because of chronic cough and bilateral infiltrates on chest roentgenogram. Additional history revealed that the patient had been taken diclofenac emulgel during the previous 10 years for arthrosis. Diagnostic bronchoscopy showed eosinophilic alveolitis. After ruling out infectious, parasitic or systemic diseases drug-induced eosinophilic pneumonia was diagnosed due to topical diclofenac therapy and subsequent percutaneous drug absorption. No previous case of eosinophilic pneumonia to topical diclofenac was discovered in our review of the literature. The diclofenac therapy was discontinued. Oral corticosteroid therapy cleared bilateral infiltrates on CT scan within seven days. Drug reactions are the most common cause of pulmonary infiltrates with blood eosinophilia and/or eosinophilic alveolitis and should be considered as a differential diagnosis.

Administration, Topical↗
PubMed2003

[Difficulties in controlled inhalation of alpha 1-protease inhibitor].

In this paper a number of studies will be summarized which were designed to improve the inhalation of alpha 1 -protease inhibitor in patients with alpha 1-protease inhibitor deficiency. A pilot study has shown that the high inter-individual variability of drug deposition in the lungs is due to heterogeneous breathing patterns of the patients. Controlling the breathing pattern led to a significantly decreased variability. Then it was studied which particle size and breathing pattern resulted in highest peripheral lung deposition in patients with emphysema. It was found that for 3 - 4 microm particles and slow inhalation flow rate the peripheral deposition increases with increasing inhalation volume. After the development of an inhalation device which allows to perform controlled inhalations in clinical practice it was shown that this device, in combination with a breathing pattern individually normalized to the patients lung function, allows to deposit nearly 60 % of the drug into the patients lung periphery.

Administration, Inhalation↗
PubMed2003

[Controlled inhalation of beta2-sympaticomimetica after bronchial provocation].

The results of several studies indicate that controlling the breathing pattern (inhaled volume and flow rate) during inhalation increases the efficacy of drug delivery to the lungs. By inhaling slowly, deeply and under controlled conditions, intrapulmonary deposition of aerosol and its reproducibility can be increased. However, it has not yet been proven that such inhalations are well tolerated by patients, especially those with airway obstructions. In this study 12 patients with mild asthma underwent a bronchial provocation test. The following broncholysis was performed with controlled, slow, and deep inhalation using the AKITA-device. The patients were asked about the convenience of this inhalation using a questionnaire. In 80 % the controlled inhalation was judged as convenient, neither as too slow nor as too fast, neither as too deep nor as too shallow. Thus it turned out that controlled deep and slow inhalations are convenient even for patients with mild airway obstruction.

Administration, Inhalation↗
PubMed2003

Peripheral deposition of alpha1-protease inhibitor using commercial inhalation devices.

Patients with hereditary alpha1-proteinase inhibitor (alpha1-PI) deficiency are at risk of developing lung emphysema. To prevent the development of this disease, alpha1-PI replacement therapy via inhalation may be a more convenient and effective therapy than the intravenous administration of the drug. In order to optimise this treatment approach, lung deposition of inhaled radiolabelled alpha1-PI (Prolastin) was studied using four different commercial inhalation devices (PARI-LC Star, HaloLite, and AKITA system in combination with LC Star and Sidestream) in six patients with alpha1-PI deficiency and mild-to-severe chronic obstructive pulmonary disease. The time required to deposit 50 mg of the Prolastin (5% solution) in the lung periphery was used as a measure for the efficiency of delivery. The time was calculated from measurements of total and peripheral lung deposition of the radiolabelled alpha1-PI. This time was shortest for the AKITA system (18-24 min) and significantly higher for the PARI-LC Star (44 min) and the HaloLite (100 min). The higher efficiency of drug delivery using the AKITA system is due to the fact that this device controls breathing patterns, which are optimised for each patient individually.

Administration, Inhalation↗
PubMed2001

Bethesda guidelines: relation to microsatellite instability and MLH1 promoter methylation in patients with colorectal cancer.

BACKGROUND: Microsatellite instability is a hallmark of mismatch repair deficiency in hereditary nonpolyposis colorectal cancer and results from mutations in the mismatch repair genes MLH1 or MSH2 or from gene inactivation associated with DNA methylation. The Bethesda guidelines were established to identify patients with colorectal cancer who should be tested for microsatellite instability. OBJECTIVE: To assess the Bethesda guidelines for detection of microsatellite instability and to determine the role of MLH1 promoter methylation in colorectal cancer. DESIGN: Prospective cohort study. SETTING: Tertiary care referral center in Frankfurt, Germany. PATIENTS: 125 consecutive patients with colorectal cancer. MEASUREMENTS: Patients were assessed according to the Bethesda guidelines, and tumor specimens were analyzed for microsatellite instability. Patients with microsatellite instability were tested for MLH1 promoter methylation and MLH1 and MSH2 germline mutations. RESULTS: Microsatellite instability was detected in 17 of 58 patients who fulfilled and 5 of 67 patients who did not fulfill criteria of the Bethesda guidelines. In 11 of 17 patients with microsatellite instability who fulfilled Bethesda guidelines, an MLH1 (n = 3), MSH2 (n = 7), or combined MLH1 and MSH2 (n = 1) mutation was found. Among the patients with microsatellite instability who did not fulfill Bethesda guidelines, no mutations were observed; MLH1 promoter methylation was observed in 6 of 11 patients with an MLH1 or MSH2 mutation and 5 of 11 patients without an MLH1 or MSH2 mutation. CONCLUSIONS: The Bethesda guidelines are useful for selecting patients for microsatellite instability testing. MLH1 and MSH2 testing should be recommended in all patients with colorectal cancer and microsatellite instability who fulfill at least one Bethesda criterion. MLH1 promoter methylation may accompany rather than initiate carcinogenesis in patients with colorectal cancer who have mismatch repair gene defects.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Gene monitoring of surface-activated monocytes in circulating whole blood using duplex RT-PCR.

Previous studies have shown that blood-contacting materials activate blood monocytes. The aim of this study is to evaluate a highly sensitive technique for detecting changes at the mRNA level in circulating monocytes and to find suitable "gene markers" for assessing the hemocompatibility of biomaterials. Human blood was recirculated in a modified Chandler Loop formed of test tubes. Five groups of biomaterials were compared. Monocytes were separated by using magnetic beads, and gene expression analyses were performed using RT-PCR. We investigated the mRNA expression of stress proteins (hsp70) and inflammatory markers (IL-1alpha, IL-1beta, IL-6, TNF-alpha). mRNAs for cytokines were highly upregulated in LPS-stimulated monocytes. Hsp70 transcripts were upregulated after heat shock but were not influenced by treatment with LPS. The gene expression of the cytokines was affected by various biomaterials. The intensity of the inflammatory response increased in the following order: heparin coatings (PVC) < uncoated PVC < silicone, polypeptide-coated PVC. No change was seen in the expression of the hsp70 genes. An inhibitory effect of systemic heparin on surface-activated monocytes was observed for the mRNA expression of the cytokines. The recirculation of human blood in an in vitro model in combination with the immunomagnetic separation of monocytes and the Duplex RT-PCR method is a powerful tool for getting reliable results. Our data demonstrate that hsp70 genes cannot be recommended for short-term, biomaterial-induced mRNA expression studies. Conversely, mRNAs for IL-1alpha, IL-1beta, IL-6, and TNF-alpha were expressed in a material-dependent manner. Thus our model provides an effective tool for assessing the hemocompatibility of biomaterials before their clinical application and it also can serve as a safety control during the industrial manufacturing process. This method can be applied to various blood cell populations and numerous gene expression studies and may enable a more fundamental understanding of the biologic processes involved in blood-material interactions.

Biocompatible Materials↗
PubMed2001

Increased sputum IL-8 and IL-5 in asymptomatic nonspecific airway hyperresponsiveness.

Since asymptomatic, nonspecific airway hyperresponsiveness (BHR) may be due to an enhanced local inflammatory response, we studied molecular markers of inflammation in induced sputum from subjects with asymptomatic BHR (n = 14) compared with control subjects (n = 13) and patients with chronic obstructive pulmonary disease (COPD) (n = 10). Pulmonary lung function parameters were measured by spirometry and body plethysmography. Hyperresponsiveness was defined based on histamine challenge. Induced sputum samples were collected and the solid phase was isolated and analyzed for leukocyte numbers and differential and for cytokines (ELISA). IL-8 was 2.4-fold increased (p = 0.036) in the sputum of subjects with asymptomatic BHR (24.8 +/- 22.0 ng/mL; +/- SD) and 11.2-fold enhanced in patients with COPD (117.8 +/- 106.3 ng/mL) as compared with control subjects (10.5 +/- 7.7 ng/mL). In control subjects, no IL-5 was measured, however, sputum of those with asymptomatic BHR contained IL-5 at 0.044 +/- 0.090 ng/mL fluid and COPD patients at 1.00 +/- 2.01 ng/mL. GM-CSF could not be detected in sputum samples of any subjects investigated. Number of total leukocytes was higher in those with asymptomatic BHR and COPD (with BHR: 9.4 +/- 10.8 x 10(5); COPD: 83.5 +/- 182.5 x 10(5)) compared with persons without BHR (2.9 +/- 3.4 x 10(5)). PMN were increased in patients with asymptomatic BHR (4.1 +/- 5.3 x 10(5)) (38.8 +/- 24.7%) and COPD (32.9 +/- 71.0 x 10(5)) (75.4 +/- 18.6%) compared with controls (0.7 +/- 0.9 x 10(5)) (25.8 +/- 25.7%). In contrast to PMN counts in those with asymptomatic BHR (0.06 +/- 0.11 x 10(5)) (1.5 +/- 3.7%), eosinophil counts were only slightly increased compared with control subjects (0.01 +/- 0.02 x 10(5)) (0.6 +/- 0.9%). This study supports the hypothesis that BHR in asymptomatic people is associated with airway inflammation that may predispose to development of chronic diseases such as COPD.

Adult↗