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Biomedical subjects

M Jung

Publications and source records attributed to M Jung.

At least 55 records · Page 3Linked to original sources
PubMed2001

Mutant Plp/DM20 cannot be processed to secrete PLP-related oligodendrocyte differentiation/survival factor.

Most of the mutations within the PLP gene result in degeneration of oligodendrocytes and this is believed to be caused by intracellular trafficking defects. Previous studies have demonstrated that cells expressing the wild type PLP gene release a factor promoting differentiation/survival of oligodendrocyte and that this factor is the C-terminal portion of the protein itself. In this study we asked how the naturally occurring mutations of the PLP gene (jimpy, jimpy msd, and rumpshaker) affect this activity. We developed a transient expression system for retroviral production and transduction that enabled the expression of mutant PLP/DM20 cDNAs in NIH3T3 cells. None of the NIH3T3 cells producing mutant PLP/DM20s secreted the PLP-related factor that increases the number of oligodendrocytes. Since it has been shown that rumpshaker DM20 can be transported to the cell surface, but its folding is incorrect, absence of secretion of this factor is more heavily attributable to incorrect protein folding than to the defect in the PLP/DM20 trafficking.

3T3 Cells↗
PubMed2001

NF-kappa B signaling pathway as a target for human tumor radiosensitization.

NF-kappa B is a critical nuclear transcriptional factor that is activated in response to cellular stresses and regulates the expression of genes involved in cell proliferation and cell death. When regulated NF-kappa B activation is disrupted, cells undergo apoptosis. That is, constitutively elevated or dysregulated NF-kappa B activation leads to cell death in response to stress. These mechanisms have been shown experimentally by expressing dominant negative inhibitors of NF-kappa B (I kappa B-alpha) in cancer cells exposed to chemotherapeutic agents or to ionizing radiation. NF-kappa B also plays an important role in a novel, radiation-inducible signaling pathway that involves the ataxia-telangiectasia mutated (ATM) protein kinase. Cells from patients with ataxia-telangiectasia (AT) are exquisitely sensitive to ionizing radiation and exhibit impaired NF-kappa B activation in response to this stress. Restoration of NF-kappa B regulation in AT fibroblasts by introducing a dominant negative form of I kappa B-alpha has resulted in correction of radiation sensitivity and a reduction of ionizing radiation-induced apoptosis. Expression of introduced ATM in AT cells results in correction of NF-kappa B regulation and an increase in postradiation survival without reduction in radiation-induced apoptosis. Taken together, these observations support a central role for NF-kappa B regulation in cellular intrinsic radiation sensitivity and apoptosis after exposure to ionizing radiation. Therefore, we hypothesize that the signaling pathway involving ATM/NF-kappa B/I kappa B offers attractive potential molecular targets for radiation sensitization in strategies to enhance the therapeutic ratio in cancer treatment.

Apoptosis↗
PubMed2001

Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon.

BACKGROUND AND STUDY AIMS: Depressed early cancers and flat adenomas have a high potential for malignancy with possible infiltrating growth, despite the small size of the lesion. Japanese investigators have shown that early diagnosis and classification of these lesions is possible with the help of chromoendoscopy. The aim of this study, therefore, was to evaluate the usefulness of chromoendoscopy during routine colonoscopy. PATIENTS AND METHODS: During routine colonoscopy, vital staining with indigocarmine solution (0.4 %, 1 - 10 ml) was performed on all visible lesions in 100 consecutive patients without visible inflammatory changes. If findings on macroscopic examination were unremarkable, the sigmoid colon and rectum were stained with indigocarmine over a defined segment (0 - 30 cm ab ano) and inspected for lesions visible only after staining. Each lesion was classified with regard to type (polypoid, flat, or depressed), position and size. The staining pattern was classified according to the pit pattern classification. RESULTS: A total of 52 patients had 105 visible lesions (89 polypoid, 14 flat and two depressed). The mean size of the lesions was 1.4 cm. Among the 48 patients with mucosa of normal appearance, 27 showed 178 lesions after staining (176 flat, two depressed) with a mean size of 3 mm. On histological investigation, 210 lesions showed hyperplastic or inflammatory changes, 67 were adenomas and six were cancers. Use of the pit pattern system to classify lesions (adenomatous, pit patterns III-V; nonadenomatous, pit patterns I-II) was possible, with a sensitivity of 92 % and a specificity of 93 %. Lesions with pit patterns III - V showed higher rates of dysplasia. CONCLUSIONS: Chromoendoscopy allows easy detection of mucosal lesions in the colon and facilitates visualization of the margins of flat lesions. This technique unmasks multiple mucosal lesions which are not identified by routine video colonoscopy. The pit pattern seen after staining allows differentiation between hyperplastic and adenomatous lesions which may have consequences with regard to the endoscopic interventions needed.

Adenoma↗
PubMed2001

[Interventional ERCP in patients with cholestasis. Degree of biliary bacterial colonization and antibiotic resistance].

Interventional ERCP in patients with cholestasis. Degree of biliary bacterial colonization and antibiotic resistance. Biliary obstruction together with bacterial colonization of the bile duct may lead to development of acute cholangitis. The aim of our prospective study was to investigate the presence and degree of biliary bacterial colonization by means of bile aspiration during ERCP in patients with biliary obstruction. Furthermore, we evaluated antibiotic therapy regimens, which would cover the bacterial species obtained by ERCP and subsequent culture in each patient. In addition, analysis of risk factors was performed that would predispose to the development of cholangitis.80 patients with clinical and laboratory evidence of biliary obstruction underwent ERCP with initial aspiration of bile via the cannulation catheter. This material was used to culture aerobic and anaerobic bacteria and determine the colony count/ml bile, followed by identification of each species and antibiotic resistance testing. The minimal inhibitory concentration for Levofloxacin, Ciprofloxacin, Piperacillin, Ampicillin, Ceftriaxone, Imipenem, Gentamycin und Metronidazole was determined. Immediately after the ERCP or if the body temperature (after ERCP) rose to > 38 degrees C blood cultures were obtained. In 45 (56 %) patients biliary colonization with bacteria could be identified (56 %). In 20 patients a single isolate was cultured, in 25 cases mixed infection was present. A total of 83 species were isolated. The most common bacteria were E. coli, Enterococcus and Klebsiella. 9.6 % of all isolates were obligatory anaerobes. In 9 of 80 patients bloodcultures tested positive for bacterial growth (rate of bacteremia: 11.3 %). 10 patients had acute cholangitis clinically before ERCP, 13 patients developed signs of infection after ERCP. Statistically significant factors contributing to the risk of infection were age of the patient, the clinical condition of the patient before ERCP and the biliary colony count. Patients with development of infection after ERCP showed a significantly higher incidence of bacterial colonization of the biliary tree and a higher colony count. In all bacterial species Imipenem (4.5 %) or Levofloxacin (2.2 %) exhibited the lowest rate of in-vitro resistance. Based on these data, the implementation of Levofloxacin in combination with anaerobic coverage is advantageous as a calculated therapy for patients with acute cholangitis.

Adult↗
PubMed2001

Screening for specialized columnar epithelium with methylene blue: chromoendoscopy in patients with Barrett's esophagus and a normal control group.

BACKGROUND: Barrett's esophagus is characterized by the presence of specialized columnar epithelium (SCE) in the distal esophagus and is a precursor for dysplasia and adenocarcinoma. Methylene blue is used to selectively stain this type of epithelium within the columnar lined distal esophagus (CLE). The goal of our prospective study was to investigate the staining pattern with methylene blue in patients with visible CLE and a control group with macroscopically normal gastroesophageal junction. METHODS: Chromoendoscopy of the distal esophagus with 1% methylene blue was performed on a total of 73 patients (51 with visible CLE, 22 normal control subjects). Biopsies were targeted toward stained or macroscopically abnormal mucosal areas. Unstained CLE was sampled by obtaining 4-quadrant biopsy specimens at 2 cm intervals. RESULTS: The targeted biopsy of stained areas provided histologic proof of SCE with a sensitivity of 98% and a specificity of 61%. The detection of SCE increased with this method in patients with visible CLE (75%), but SCE was also prevalent in the control group (73%). Areas that by their appearance raised a suspicion for dysplasia and adenocarcinoma were already endoscopically apparent in 3 of 4 cases before methylene blue staining and showed different staining patterns. CONCLUSIONS: Methylene blue staining increases the rate of detection of SCE, both in patients with visible CLE and with normal gastroesophageal junction. For detection of dysplastic or malignant areas it is important to look for visible mucosal changes.

Aged↗
PubMed2001

A dominant modifier of transgene methylation is mapped by QTL analysis to mouse chromosome 13.

The single-copy hepatitis B virus transgene in the E36 transgenic mouse strain undergoes methylation changes in a parent-of-origin, tissue, and strain-specific fashion. In a C57BL/6 background, the paternally transmitted transgene is methylated in 30% of cells, whereas it is methylated in more than 80% of cells in (BALB/c x C57BL/6) F1 mice. We established previously that several genetic factors were likely to contribute to the transgene methylation profile, some with demethylating and some with de novo methylating activities. Using quantitative trait loci (QTL) mapping, we have now localized one major modifier locus on chromosome 13 (Mod13), which explains a 30% increase in the methylation level of this transgene with no effect on the flanking endogenous sequences. No other QTL could be identified, except for a demethylating activity of low significance located on chromosome 12. Recombinant inbred mice containing a BALB/c allele of Mod13 were then used to show that the presence of Mod13 is sufficient to induce de novo methylation. A segregation between de novo methylation and repression of transgene expression was uncovered, suggesting that this genetic system is also useful for the identification of factors that interpret methylation patterns in the genome.

Animals↗
PubMed2001

Feasibility of a semiconductor dosimeter to monitor skin dose in interventional radiology.

The design and preliminary test results of a semiconductor silicon dosimeter are presented in this article. Use of this dosimeter is foreseen for real-time skin dose control in interventional radiology. The strong energy dependence of this kind of radiation detector is well overcome by filtering the silicon diode. Here, the optimal filter features have been calculated by numerical Monte Carlo simulations. A prototype has been built and tested in a radiological facility. The first experimental results show a good match between the filtered semiconductor diode response and an ionization chamber response, within 2% fluctuation in a 2.2 to 4.1 mm Al half-value layer (HVL) energy range. Moreover, the semiconductor sensor response is linear from 0.02 Gy/min to at least 6.5 Gy/min, covering the whole dose rate range found in interventional radiology. The results show that a semiconductor dosimeter could be used to monitor skin dose during the majority of procedures using x-rays below 150 keV. The use of this device may assist in avoiding radiation-induced skin injuries and lower radiation levels during interventional procedures.

Air↗
PubMed2001

Improvement in diabetes control with a monitoring system based on a hand-held, touch-screen electronic diary.

We conducted a six-month prospective interventional crossover study examining a computerized diabetes monitoring system (DMS) that conveyed dietary information. The objectives were to compare glycaemic control between intervention and control periods, and to assess patients' acceptance of the DMS. Nineteen patients were randomized into two groups, each using the DMS for three months and serving as the control group for another three months. The patients recorded information about their meal portions and blood glucose readings in a hand-held electronic diary. After transmitting the data to the DMS through a telephone modem, the patients received immediate feedback about the carbohydrate, protein and fat content of the meal, as well as the calorie content. A significant improvement in glycaemic control was achieved during intervention compared with control periods (mean HbA1C reduction of 0.825%). The DMS was also highly acceptable: 95% patients found it easy to operate while 63% found it useful. The DMS was thus a feasible model of telemedicine in diabetes care and a larger study is warranted to examine its cost-effectiveness.

Adult↗
PubMed2001

Inhibitors of histone deacetylase as new anticancer agents.

Inhibitors of histone deacetylase (HDAC) are an emerging class of anticancer agents. They induce hyperacetylation in chromatin usually resulting in activation of certain genes. They induce terminal cell differentiation and/or apoptosis in cancer cells. Histone deacetylase activity is recruited by co-repressor proteins to certain regions of the chromatin and aberrant histone acetylation caused by that recruitment is responsible for the pathogenesis of certain cancers on a molecular level. Inhibitors of HDAC have been identified in natural sources and also synthetic inhibitors are available. The best studied inhibitor is trichostatin A, a hydroxamic acid that exerts its activity by complexation of a zinc ion that is supposed to mediate the acetamide cleavage at the catalytic site. There are several synthetic hydroxamic acids that bear resemblance to trichostatin. Another class of potent inhibitors are naturally occurring and synthetic cyclotetrapeptides that all contain an unusual amino acid with an epoxyketone, ketone or hydroxamic acid function in the side chain. Phenylacetate, phenylbutyrate, butyrate and similar short chain fatty acids are also weak inhibitors. Further inhibitors from natural sources are the epoxide depudecin and depsipeptide FR 901228. The benzamide MS-275 belongs to a new class of synthetic HDAC inhibitors and displays oral activity in animal models. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer is possible. Thus, inhibitors of HDAC are one of the most promising class of new anticancer agents. New screening assays are useful tools that will facilitate identification of further inhibitors.

Anti-Bacterial Agents↗
PubMed2001

Antibody directed enzyme prodrug therapy (ADEPT) and related approaches for anticancer therapy.

In antibody directed enzyme prodrug therapy (ADEPT) an antibody bound enzyme is targeted to tumor cells. This allows for selective activation of a nontoxic prodrug to a cytotoxic agent at the tumor site for cancer therapy. Site-selective prodrug activation results in reduced side effects in remote tissue. This article reviews ADEPT with emphasis on the chemical viewpoint and recent developments.

Animals↗
PubMed2001

A growth and differentiation factor-5 (GDF-5)-coated suture stimulates tendon healing in an Achilles tendon model in rats.

Growth and differentiation factor-5 (GDF-5) is essential for normal skeletal development and induces tendon-and ligament-like structures at ectopic sites. Therefore, we investigated the influence of a GDF-5-coated suture on the healing Achilles tendon in rats. The right Achilles tendon in 80 rats was transected and sutured with an absorbable polyglactin suture. Animals were randomized to an uncoated-suture control and a GDF-5-coated suture group. At 1, 2, 4 and 8 weeks after surgery the repair tissue was evaluated biomechanically and histologically. Biomechanical testing revealed significantly thicker tendons, which were stiffer at 1, 2, and 4 weeks, in the experimental group than in the control group. The maximum tensile strength was significantly increased at 2 weeks after surgery. Histologically we found cartilage-like cell nests 4 weeks after tendon repair, which were positive for type II collagen. In conclusion, local growth factor delivery by a coated suture material showed a promising beneficial effect on tendon repair. The appearance of cartilage-like structures may demonstrate the chondroinductive capacity of GDF-5, which in these circumstances, however, might be overcome by modifications of the GDF-5 dose and/or the suture material.

Achilles Tendon↗
PubMed2001

Selective blockade of neurokinin-2 receptors produces antidepressant-like effects associated with reduced corticotropin-releasing factor function.

The present study investigated the effects of the selective neurokinin-2 (NK2) receptor antagonist SR48968 in behavioral, electrophysiological, and biochemical tests sensitive to the action of prototypical antidepressants (fluoxetine, imipramine) or to corticotropin-releasing factor (CRF) receptor antagonists, which have been proposed recently as potential antidepressants. Results showed that SR48968 (0.3-10 mg/kg i.p.) produced antidepressant-like activity because it reduced immobility in the forced swimming test in both mice and rats, and decreased the amount of maternal separation-induced vocalizations in guinea pig pups. This latter effect appears to involve a reduction of stress-induced substance P release because SR48968 reduced the separation-induced increase in the number of neurons displaying neurokinin-1 receptor internalization in the amygdala. Furthermore, SR48968 increased the expression of the cAMP response-element binding protein mRNA in the rat hippocampus after repeated (1 mg/kg i.p., 21 days), but not acute administration. Finally, neuronal firing of the locus coeruleus (LC) and noradrenergic (NE) release in the prefrontal cortex both elicited by an uncontrollable stressor or an intraventricular administration of CRF were reduced by SR48968 (0.3-1 mg/kg i.p.). The finding that SR48968 (1 mg/kg i.p.) blocked the cortical release of NE induced by an intra-LC infusion of the preferential NK2 receptor agonist neurokinin A suggested the presence of NK2 receptors in this latter region. Importantly, SR48965 (1-10 mg/kg i.p.), the optical antipode of SR48968, which is devoid of affinity for the NK2 receptor, was inactive in all the models used. These data suggest that NK2 receptor blockade may constitute a novel mechanism in the treatment of depression and CRF-related disorders.

Animals↗
PubMed2001

Localization of individual subunits of protein kinase CK2 to the endoplasmic reticulum and to the Golgi apparatus.

The protein kinase CK2 is composed of two catalytic alpha- or alpha'- and two regulatory beta-subunits. In mammalian cells there is ample evidence for the presence of individual CK2 subunits beside the holoenzyme. By immunofluorescence studies using peptide antibodies which allow us to detect the CK2alpha-, alpha'- and beta-subunits we found all three subunits to be co-localized with a 58 KDa Golgi protein which is specific for the Golgi complex. Subfractionation studies using dog pancreas cells revealed the presence of all three subunits of CK2 at the smooth endoplasmic reticulum (sER)/Golgi fraction whereas the rough endoplasmic reticulum (rER) harboured only the catalytic alpha- and alpha'-subunits. We found that the microsomal preparation from dog pancreas cells contained CK2 which phosphorylated a CK2 specific synthetic peptide and which was heparin sensitive. Furthermore, we could immunoprecipitate the CK2alpha-subunit that exhibited a kinase activity which phosphorylated a CK2 specific substrate and which was heparin sensitive. Protease digestion experiments revealed that the CK2 subunits were located on the cytosolic side of the rER and the sER/Golgi complex. Thus, we could demonstrate an asymmetric distribution of the CK2 subunits at the rER and sER/Golgi complex. Since the CK2alpha- and alpha'-subunits exhibit a substrate specificity which is different from the CK2 holoenzyme one might speculate that the asymmetric distribution of the CK2 holoenzyme and the CK2 catalytic subunits may have regulatory functions.

Animals↗
PubMed2000

A novel form of "central pouchlike" cataract, with sutural opacities, maps to chromosome 15q21-22.

Congenital cataract is a clinically and genetically highly heterogeneous eye disorder, with autosomal dominant inheritance being most common. We investigated a large seven-generation family with 74 individuals affected by autosomal dominant congenital cataract (ADCC). The phenotype in this family can be described as "central pouchlike" cataract with sutural opacities, and it differs from the other mapped cataracts. We performed linkage analysis with microsatellite markers in this family and excluded the known candidate genes. A genomewide search revealed linkage to markers on chromosome 15, with a maximum two-point LOD score of 5.98 at straight theta=0 with marker D15S117. Multipoint analysis also gave a maximum LOD score of 5.98 at D15S117. Multipoint and haplotype analysis narrowed the cataract locus to a 10-cM region between markers D15S209 and D15S1036, closely linked to marker D15S117 in q21-q22 region of chromosome 15. This is the first report of a gene for a clinically new type of ADCC at 15q21-22 locus.

Cataract↗
PubMed2000

CALEB binds via its acidic stretch to the fibrinogen-like domain of tenascin-C or tenascin-R and its expression is dynamically regulated after optic nerve lesion.

Recently, we described a novel chick neural transmembrane glycoprotein, which interacts with the extracellular matrix proteins tenascin-C and tenascin-R. This protein, termed CALEB, contains an epidermal growth factor-like domain and appears to be a novel member of the epidermal growth factor family of growth and differentiation factors. Here we analyze the interaction between CALEB and tenascin-C as well as tenascin-R in more detail, and we demonstrate that the central acidic peptide segment of CALEB is necessary to mediate this binding. The fibrinogen-like globe within tenascin-C or -R enables both proteins to bind to CALEB. We show that two isoforms of CALEB in chick and rodents exist that differed in their cytoplasmic segments. To begin to understand the in vivo function of CALEB and since in vitro antibody perturbation experiments indicated that CALEB might be important for neurite formation, we analyzed the expression pattern of the rat homolog of CALEB during development of retinal ganglion cells, after optic nerve lesion and during graft-assisted retinal ganglion cell axon regeneration by in situ hybridization. These investigations demonstrate that CALEB mRNA is dynamically regulated after optic nerve lesion and that this mRNA is expressed in most developing and in one-third of the few regenerating (GAP-43 expressing) retinal ganglion cells.

Amino Acid Sequence↗