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Biomedical subjects

Christian Müller

Publications and source records attributed to Christian Müller.

At least 37 records · Page 2Linked to original sources
PubMed2006

Chronic Hepatitis B and C--current treatment and future therapeutic prospects.

In chronic hepatitis B treatment with pegylated interferon can now be considered as therapy of choice in both HBeAg positive and HBeAg negative patients and seems to be more effective than lamivudine monotherapy. Alternatively, treatment with lamivudine is able to suppress HBV DNA and to induce HBeAg conversation in up to 30 % of the patients. In HBeAg negative chronic hepatitis B lamivudine has a similar efficiency in suppressing HBV DNA as in HBeAg positive patients. The frequently developing lamivudine resistant HBV variants can now be successfully be treated with adevofir dipivoxil in both forms of chronic hepatitis B. These nucleosides analogues are generally better tolerated than interferon and can also be given in patients with HBV related liver cirrhosis. Our therapeutic armamentarium will be expanded in the near future by other nucleoside analogues such as entecavir, emtricitapine, telbivudine or clevudine. The treatment of choice in chronic hepatitis C currently is pegylated interferon plus ribavirin. This regimen is able to induce a sustained virologic response in 50 % of treatment naïve cases. The limited effectiveness of this therapeutic approach makes additional drugs highly warranted and inhibitors of the NS3-4a protease region or the NS5B polymerase region of the viral genome are under development. In addition, HCV replication inhibitors based on RNA interference (siRNA) or agonists of toll like receptors (TLR), which are part of the inborn immune system recognizing the presence of invading microorganisms, are currently explored as agents active in inhibiting HCV replication. Although none of these drugs are currently licensed for HCV treatment they are promising antiviral candidates for the future.

Adenine↗
PubMed2006

Hepatocellular carcinoma--rising incidence, changing therapeutic strategies.

Despite considerable efforts no ideal treatment exists for HCC. The disease is usually detected late and few patients are candidates for potentially curative treatment options such as surgical resection or liver transplantation. Surgical resection is limited mostly by the impaired liver function in cirrhotic livers, whereas liver transplantation is limited by tumor size, multi-localized disease and, most important, by shortage of donor organs. TACE as a local ablative treatment is able to induce local disease control and to prolong survival and might even achieve survival similar to surgical resection. The high rates of recurrence of HCC after successful control of local tumor spread is the reason to consider that procedure as a non-curative treatment option. PEI and RFA are able to control local tumor growth, but cannot influence tumor recurrence or de novo tumor growth. Systemic therapies need to be investigated in large randomized trials, especially to evaluate the use of somatostain analogues, HMGCoA reductase inhibitors, or other drugs such as rapamycin or inhibitors of vascular endothelial growth factor (VEGF).

Carcinoma, Hepatocellular↗
PubMed2006

Liver, alcohol and gender.

Gender differences in alcohol-induced liver injury have been well described. Females develop alcoholic liver injury more rapidly and have a lower alcohol toxic threshold than men. The mechanism for this difference is poorly characterized, differences in first-pass metabolism in the stomach, or elimination rate, or alcohol distribution volume in the body have been suggested. In addition, estrogen has a major influence on the susceptibility of Kupffer cells to gut-derived LPS resulting in increased proinflammatory cytokine production, which could be a major contributing factor to the increased risk of women to alcohol-induced liver disease.

Alcoholic Intoxication↗
PubMed2006

The combined elevation of tumor markers CA 19-9 and CA 125 in liver disease patients is highly specific for severe liver fibrosis.

Increased tumor markers in patients with liver cirrhosis are often considered to be unspecific. The use of this unspecific elevation to discriminate minimal fibrosis from severe fibrosis has never been explored. We aimed to answer the question, Do tumor markers predict severe liver fibrosis? The study group consisted of 125 patients with alcoholic liver disease, hepatitis B, or hepatitis C with available liver biopsy. Tumor markers CA 19-9, CA 15-3, and CA 125 were determined using routine laboratory methods and correlated with the extent of liver fibrosis. Fibrosis stages 1 and 2 were classified as minimal fibrosis; stages 3 and 4, as severe fibrosis. Tumor markers CA 19-9, CA 125, and CA 15-3 increased with stage of fibrosis. For separating patients with mild fibrosis (F1+F2) from patients with severe fibrosis (F3+F4), CA 19-9 had a sensitivity of 70.5% and a specificity of 88.6, CA 125 had 38.1% and 89.7%, and CA 15-3 had 19.0% and 93.0%, respectively. Logistic regression of a combined score of CA19-9 and CA 125 values revealed that an increase of 1 point of the CA 19-9/CA125 score resulted in a 1.6 times increase in likelihood of the presence of severe fibrosis. The CA 19-9/CA 125 score achieved a similar specificity (97.1% vs. 100%) but a higher sensitivity (42.9% vs. 33.3%) than the widely used cirrhosis discriminant score of Bonacini. A specificity (98.5%) similar to that of the CA 19-9/CA 125 score was reached by the easier determination of the combined elevation of CA 19-9 and CA 125, which had the best positive predictive value, 92.9%. The excellent predictive ability of the combined elevation of CA 19-9 and CA 125 for severe liver fibrosis (F3+F4) was confirmed in an independent group of patients with liver disease. The combined elevation of CA 19-9 and CA 125 is useful for identifying patients with advanced fibrosis or cirrhosis with high specificity. Patients without a combined elevation of CA 19-9 and CA 125 still require histological examination to identify severe fibrosis or cirrhosis.

Adolescent↗
PubMed2006

Enhanced IgE allergic response to Aspergillus fumigatus in CFTR-/- mice.

To gain insight into aberrant cytokine regulation in cystic fibrosis (CF), we compared the phenotypic manifestations of allergen challenge in gut-corrected CFTR-deficient mice with background-matched C57Bl6 (B6) mice. Aspergillus fumigatus (Af) antigen was used to mimic allergic bronchopulmonary aspergillosis, a peculiar hyper-IgE syndrome with a high prevalence in CF patients. CFTR-/-, C57BL/6 and FVB/NJ mice were sensitized with Af antigen by serial intraperitoneal injections. Control mice were mock sensitized with PBS. Challenges were performed by inhalation of Af antigen aerosol. After Af antigen challenge, histologic analysis showed goblet cell hyperplasia and lymphocytic infiltration in both strains. However, total serum IgE levels were markedly elevated in CF mice. Sensitized CF mice showed a five-fold greater IgE response to sensitization as compared with B6- and FVB-sensitized controls. Additional littermate controls to fully normalize for B6-FVB admixture in the strain background confirmed the role of CFTR mutation in the hyper-IgE syndrome. Cytokine mRNA levels of IL-5 and GM-CSF in the bronchoalveolar lavage (BAL) fluid, and BAL cell differentials indicated that CFTR mutation caused a shift from an IL-5-predominant to an IL-4-predominant cytokine profile. This system models a very specific type of airway inflammation in CF and could provide insights into pathogenesis and treatment of the disease.

Allergens↗
PubMed2006

Mutation of keratin 8 in patients with liver disease.

BACKGROUND: Epithelial tissues of the gastrointestinal tract and the liver express predominantly cytokeratin 8 and cytokeratin 18. In vitro experiments and animal studies have demonstrated a protective influence of keratin 8 and keratin 18 against toxic damage of hepatocytes. A specific mutation of keratin 8 (G61C) was found to be a genetic risk factor for the development of cryptogenic liver cirrhosis. The purpose of the present paper was therefore to determine the prevalence of cytokeratin 8 (G61C) and cytokeratin 18 mutations (Y53H) in patients with liver disease. METHODS: Overall 152 patients (male, n = 93, 61%; female, n = 59, 39%) were included in the present study. The 152 patients consisted of 107 patients with liver disease (70.4%; male, n = 71, 66.4%; female, n = 36, 33.6%) and 45 control patients (29.6%; male, n = 22, 48,9%; female, n = 23, 51,1%) without liver disease. Of the patients with liver disease 46 had alcoholic liver disease; 25, chronic hepatitis C; 15, cryptogenic liver disease; and 21, other liver diseases of various etiologies. Cytokeratin 8 and 18 genotypes were specified by polymerase chain reaction (PCR) amplification and direct sequence analysis was used to detect the previously described mutations in cytokeratin 8 (G61C) and in cytokeratin 18 (Y53H). RESULTS: Four out of 152 patients (male n = 2, female n = 2) with a mutation (G61C) in cytokeratin 8 were found. The etiology was alcoholic liver disease (n = 1), cryptogenic liver disease (n = 1) and idiopathic liver disease with minimal changes in liver biopsy (n = 1). Also, one out 45 disease control patients with an adenoma of the colon but without liver disease was found to carry the mutation G61C of cytokeratin 8. Therefore, the mutation G61C in cytokeratin 8 was found in 2.8% of patients with liver disease and in 2.2% of control patients without liver disease. Two of 15 patients (13.3%) with cryptogenic liver disease had the mutation G61C in cytokeratin 8 (P = 0.069 vs patients with non-cryptogenic liver disease). In the 152 patients studied, no mutation in cytokeratin 18 was found. DISCUSSION: The mutation G61C in the cytokeratin 8 gene was found in one patient with alcoholic liver disease and in two patients with liver disease of unknown etiology. Also, one patient without liver disease had the cytokeratin 8 G61C mutation. In summary, the cytokeratin 8 mutation G61C, which has been found to be associated with cryptogenic liver cirrhosis, was also found in the present patient population. However, the clinical relevance is yet to be determined in further investigations.

Animals↗
PubMed2006

Evaluation of primary human liver cells in bioreactor cultures for extracorporeal liver support on the basis of urea production.

Primary human liver cells from donor organs unsuitable for transplantation were cultivated in bioreactors developed for extracorporeal liver support. Because each system contains cells originating from an individual organ, each bioreactor culture must be individually characterized. The objective of this study was to identify suitable decisive parameters for the evaluation of cell culture performance. We analyzed the data from 47 bioreactor cultures containing 437 +/- 110 g of cells. Choosing urea production as the decisive parameter, the bioreactor cultures were divided into high-performance (daily urea production > or = 110 mg per bioreactor between culture days 3 and 14) and low-performance cultures. Comparing the mean courses of the groups revealed a significant distinction in most other investigated biochemical parameters. In conclusion, urea production seems to be an appropriate parameter for evaluating the performance of liver cell cultures in bioreactors because it corresponds to all other evaluated parameters of cell function.

Adult↗
PubMed2006

Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment.

OBJECTIVES: Myeloma bone disease is a result of excessive osteoclast activation and impaired osteoblast function. Recent in vitro studies suggested that proteasome inhibitors might increase osteoblast function. METHODS: We analyzed serum markers of osteoblast activity in 25 patients with multiple myeloma receiving bortezomib alone or in combination with dexamethasone. As control, serum samples from 58 consecutive myeloma patients receiving a therapy different than bortezomib (i.e. adriamycin/dexamethasone, melphalan/prednisone or thalidomide) were evaluated. The serum concentrations of bone-specific alkaline phosphatase (BAP) and osteocalcin were quantified before initiation of treatment and after 3 months. RESULTS: In patients treated with bortezomib, mean serum levels of osteocalcin significantly increased from 6.3 to 10.8 microg/L (P = 0.024), while mean BAP levels increased from 19.7 to 30.2 U/L (P < 0.0005). Of interest, the increase in BAP was significant both in responders and non-responders. In contrast, the control group did not show a statistically significant change in BAP (24.8 U/L vs. 23.3 U/L) and osteocalcin (6.8 microg/L vs. 6.5 microg/L) before and after the treatment. CONCLUSION: These data show that treatment with bortezomib leads to enhanced markers of osteoblast activity in patients with myeloma. The comparison with the control group suggests that the effect on osteoblasts is unique to the proteasome inhibitor.

Adult↗
PubMed2006

Downregulation of aquaporins 1 and 5 in nasal gland by osmotic stress in ducklings, Anas platyrhynchos: implications for the production of hypertonic fluid.

Using primers against highly conserved regions of mammalian and bird aquaporins in RT-PCR experiments, we amplified products derived from duck (Anas platyrhynchos) nasal gland RNA that were identified as homologues of mammalian and chicken aquaporin 1 and aquaporin 5 cDNAs by sequencing. Using digoxigenin-labelled probes derived from these PCR products in northern blot analyses of mRNA isolated from nasal glands of untreated (naïve) or osmotically stressed ducklings (replacement of drinking water with a 1% NaCl solution), we observed a decrease in aquaporin 1 (AQP1) and aquaporin 5 (AQP5) mRNA abundance (by approximately 40%) during saline adaptation in the animals. Western blot analysis of AQP1 and AQP5 expression in the glands revealed that protein abundance decreased in a similar fashion. Immunohistochemical analysis of AQP1 distribution in cryosections of nasal gland indicated that AQP1 is mainly expressed in endothelial cells of the capillaries, but definitely not in the secretory or ductal cells of the gland. AQP5 distribution in the gland, however, seems to be different, since staining was exclusively observed in apical and basolateral plasma membranes of individual epithelial cells of the primary and central ducts, which collect fluid from the secretory tubules. The observations are consistent with the hypothesis that strongly hyperosmotic fluid is produced by the secretory cells at very low (unstimulated gland) or high (activated gland) rates. In the unstimulated gland, secretions may be diluted by aquaporin-mediated transcellular water flux while passing through the ductal system flushing the glandular ducts, thereby potentially preventing ascending infections. In the activated gland, however, downregulation of aquaporins in capillaries and duct cells may prevent dilution of the initially secreted fluid, enabling the animals to excrete large volumes of a highly concentrated salt solution.

Amino Acid Sequence↗
PubMed2006

Interchangeability of measurements of total and free prostate-specific antigen in serum with 5 frequently used assay combinations: an update.

BACKGROUND: The comparability of total and free prostate-specific antigen (tPSA and fPSA) results among commercial PSA assays has been suggested to be improved by calibration to WHO PSA reference materials and the development of equimolar-response assays. To characterize the current situation, we assessed 5 frequently used commercial assay combinations for tPSA and fPSA regarding the interchangeability of the PSA values and the ratio of fPSA to tPSA (%fPSA), equimolar characteristics, and diagnostic accuracy. METHODS: Sera from 314 patients with prostate cancer (PCa) and 282 men with no evidence of prostate cancer (NPCa) were measured with tPSA and fPSA assays from Abbott (AxSYM), Beckman Coulter (Access), Diagnostic Products Corporation (Immulite 2000), and Roche (Elecsys 2010) and with tPSA and complexed PSA (cPSA) assays from Bayer (ADVIA Centaur). RESULTS: Method comparisons (Passing and Bablok regressions; Bland-Altman plots) showed assay-dependent results for tPSA, fPSA, and %fPSA. With the Access tPSA values taken as 100%, tPSA concentrations varied from 87% (AxSYM and ADVIA Centaur) to 115% (Immulite), leading to different numbers of patients classified according to the commonly recommended tPSA cutoffs for performing a biopsy. Different %fPSA values also led to assay-dependent ROC analysis results, a finding that shows the importance for the diagnostic accuracy. CONCLUSION: Interchangeability of tPSA, fPSA, and %fPSA values obtained by commercial PSA assays remains inadequate, but attention to this issue may minimize the misinterpretation of PSA results obtained by different assays.

Adult↗
PubMed2006

[Asylum for curing or securing? The confinement of forensic patients as a challenge of asylum psychiatry in Imperial Germany].

Asylum for curing or securing? The confinement of forensic patients as a challenge of asylum psychiatry in Imperial Germany. In Imperial Germany psychiatrists sought to give their asylums the character of modern medical hospitals. Due to the increase of insanity defence these efforts were obstructed by the high number of inmates with a criminal background. Special departments for mentally ill criminals were founded both in asylums and in prisons. But the clientele was not welcome in any of these institutions. Thus, there was a high fluctuation between prisons and asylums. A new definition of criminal responsibility was needed. In order to keep criminals out of their hospitals psychiatrists developed the medical concept of psychopathy referring to a mental defect without lack of responsibility. On the other hand penal law reformers plead to introduce preventive measures, such as security confinement, into the criminal law book. Since the resolution of the 'law against habitual criminals' in November 1933 judges are allowed to sentence mentally ill offenders to indefinite confinement in psychiatric institutions.

Forensic Psychiatry↗
PubMed2005

cycloSal-PMEA and cycloAmb-PMEA: potentially new phosphonate prodrugs based on the cycloSal-pronucleotide approach.

Two new classes of lipophilic prodrugs of the antiviral active phosphonate 9-[2-phosphonomethoxyethyl]adenine (PMEA 1) have been prepared and were studied with regard to their hydrolysis properties and biological activity. A first series of compounds was prepared on the basis of the cycloSal nucleotide approach. Because of the surprisingly low hydrolysis stability of these cycloSal-PMEA derivatives, more stable derivatives have to be developed. Instead of using salicyl alcohol, in cycloAmb-PMEA derivatives 2-aminobenzyl alcohols were attached to PMEA 1. The latter compounds showed a considerably higher stability compared to the cycloSal counterparts. Stability studies revealed that all lipophilic prodrugs delivered PMEA selectively by chemical means. All compounds proved to be noninhibiting to acetyl- and butyrylcholinesterase, and some of the phosphonate diesters were found to be more active against HIV compared to the parent PMEA.

Acetylcholinesterase↗
PubMed2005

Urinary S-100B concentrations in term and preterm infants at risk for brain damage.

BACKGROUND: Elevated serum concentrations of S-100B, a 21-kDa protein expressed in astroglial cells, has been used to assess cerebral damage after head trauma, infection, ischemia, and perinatal asphyxia. OBJECTIVE: As S-100B is eliminated by the kidneys, we investigated the feasibility of measuring S-100B in urine of newborns with severe perinatal asphyxia, and in very low birth weight (VLBW) preterm infants at risk for neurodevelopmental impairment. METHODS: We first analyzed urine samples of 8 term or near-term newborns without major medical problems, followed by urine samples of 2 term newborns with severe birth asphyxia, and finally urine samples of 8 VLBW (gestational age 24-28 weeks) infants collected every 4 h for up to 10 days. RESULTS: Urinary S-100B concentrations in 8 term or near-term newborns without major medical problems were consistently <1 microg/l. In 2 term newborns with severe asphyxia (Apgar 0/0/0 and 0/2/4) who subsequently had widespread cerebral damage on magnetic resonance imaging, peak urinary S-100B concentrations on the first day of life were 28.1 and 28.4 microg/l, respectively. In 5/8 VLBW infants, urinary S-100B was> microg/l in samples obtained on the first day of life (range 1.2-44.9 microg/l, median 6.8 microg/l). Peak S-100B in urine samples collected during the first 12 h of life were negatively related to gestational age (R(s)=-0.882, p=0.009). Three of the 8 preterm infants had peak urinary concentrations>0 microg/l but neither ultrasound signs of brain damage nor neurodevelopmental delay at 1 year corrected age. CONCLUSIONS: The determination of urinary S-100B concentrations might be helpful in term infants with severe asphyxia, while high urinary S-100B concentrations in preterm infants are to be attributed to immaturity.

Brain↗
PubMed2005

Singing icebergs.

Sustained harmonic tremor signals were recorded by the seismographs of the German Neumayer Base seismological network in western Dronning Maud Land, Antarctica. These tremor episodes, lasting up to 16 hours, were recorded up to 820 kilometers from the source. Their spectra show narrow peaks with fundamental frequencies ranging from 0.5 to 6 hertz, more than 30 integer harmonic overtones, and frequency gliding, resembling volcanic tremor. Frequency-wave number analysis suggested a moving source, which was recognized as iceberg B-09A traveling along the coast of eastern Antarctica. The most probable tremor sources are fluid-flow-induced vibrations inside the iceberg's tunnel/crevasse systems.

Journal Article↗
PubMed2005

Attenuation of cell cycle regulator p27(Kip1) expression in vertebrate epithelial cells mediated by extracellular signals in vivo and in vitro.

Cell cycle arrest in potentially dividing cells is often mediated by inhibitors of G1/S-phase cyclin-dependent kinases. The cyclin E/CDK2-inhibitor p27(Kip1) has been implicated in this context in epithelial cells. We cloned and sequenced p27(Kip1) of ducklings (Anas platyrhynchos) and used an in vitro assay system to study the mechanism of p27(Kip1) downregulation in the nasal gland which precedes an increase in proliferation rate upon initial exposure of the animals to osmotic stress. Western blot studies revealed that p27(Kip1) is downregulated during 24 h of osmotic stress in ducklings with the steepest decline in protein levels between 5 and 8 h. As indicated by the results of Northern blot and semi-quantitative PCR studies, protein downregulation is not accompanied by similar changes in mRNA levels indicating that Kip1 is regulated mainly at the translational (synthesis) or posttranslational level (degradation). Using recombinant duck Kip1 protein expressed in E. coli, we showed that Kip1 is subject to polyubiquitinylation by cytosolic enzymes from nasal gland cells indicating that loss of Kip1 may be regulated, at least in part, by acceleration of protein degradation. In cultured nasal gland tissue, attenuation of Kip1 expression could be induced by activation of the muscarinic acetylcholine receptor indicating that mAChR-receptor signalling may play a role in the re-entry of quiescent gland cells into the cell cycle.

Amino Acid Sequence↗
PubMed2005

Second-line chemotherapy of advanced disseminated gastric cancer after cisplatin, infusional 5-fluorouracil, folinic acid (PLF): benefit dependent on progression-free interval after first-line therapy.

BACKGROUND: The role of second-line chemotherapy in gastric cancer is not yet established. We analyzed patients receiving second-line treatment after chemotherapy with cisplatin, infusional 5-fluorouracil, folinic acid (PLF). PATIENTS AND METHODS: 27 patients took part in this retrospective analysis. The second-line chemotherapy consisted of different regimens depending on the recommendations of the attending physician based on response to and toxicity of first-line treatment. RESULTS: In 3 of 27 patients, partial response was achieved (11%, 95%-confidence interval 0-23%). The progression-free survival and overall survival was 3.1 (2.1-4.3) and 5.1 (3.8-6.6) months, respectively. Progression-free intervals (PFI) of more than 7 months after first-line therapy were a predictor for patients who may benefit from the treatment (median survival from the start of second-line therapy: 10.6 (6.6-13.1) months). CONCLUSION: Second-line chemotherapy after cisplatin / 5-FU rarely induced tumor response, and progression-free survival as well as overall survival remained short. Based on our data, we hypothesize that the PFI after first-line treatment may be a selection criterion for patients suitable for second-line chemotherapy.

Adenocarcinoma↗
PubMed2005

Crystalline-crystalline block copolymers of regioregular poly(3-hexylthiophene) and polyethylene by ring-opening metathesis polymerization.

Block copolymers of regioregular poly(3-hexylthiophene) (P3HT) and polyethylene (PE) were synthesized through the chain transfer of olefin-terminated P3HT in the presence of cyclooctene via ring-opening metathesis polymerization (ROMP). Subsequent hydrogenation of the poly(cyclooctene) block yielded high molecular weight, crystalline-crystalline P3HT-PE block copolymers, which are thermally stable and resistant to solvents under ambient conditions. These copolymers were characterized by 1H NMR, DSC, and WAXS and represent the first materials of a class of crystalline-crystalline semiconducting-insulating block copolymers.

Calorimetry, Differential Scanning↗