Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B.
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Animals↗
Biomedical subjects
M Jung
Publications and source records attributed to M Jung.
Role of the specific T-cell response for clearance and control of hepatitis C virus.
T cells are believed to be the main players in antiviral defence. To investigate the role of the specific CD4+ T cell response for clearance and control of the hepatitis C virus we studied patients with acute hepatitis C (AHC) during the phase of spontaneous viral clearance and during follow up after elimination of the virus and resolution of disease. Symptomatic AHC has a self-limited course in 50% of patients, whereas the other half show virus persistence and develop chronic course of disease. Patients who were able to mount a vigorous, polyclonal, multispecific, TH1 lymphokine dominated CD4+ T-cell response showed viral clearance and a self-limited course of disease. In contrast, absence of this T-cell response in patients with AHC invariably led to viral persistence and chronic hepatitis. The characteristics of the T-cell response were as follows: it was mainly directed against nonstructural proteins of the virus, it was multispecific and demonstrated immunodominant epitopes, and the majority of T-cell clones established from our patients responded to a single peptide (NS3 amino acid 1248-1261) within the helicase region of HCV. Presentation of the peptide was HLA DR specific, the peptide showed promiscuous binding, and it had high binding affinity to 10 of the most common 13 HLA DR alleles, thus patients with diverse HLA DR backgrounds could mount an immune response. Furthermore, the epitope was conserved in 100% of 33 HCV strains published in databases. This strong initial CD4+ T-cell response is not sufficient for a definitive recovery from AHC, it has to be maintained to control the hepatitis C virus. Loss of the response after initial resolution of disease is followed by relapse. Even 20 years after an episode of self-limited AHC with elimination of HCV, we have observed a significant virus-specific CD4+ T-cell response. Our data indicate the decisive role of the virus-specific CD4+ T-cell response for clearance and control of HCV, and contribute to our understanding of immune mechanisms by which the host defends the HCV virus. This is a prerequisite for the development of new strategies to efficiently defend the virus by manipulating or modulating the immune response.
CD4-Positive T-Lymphocytes↗
Chromoendoscopy and intravital staining techniques.
Chromoendoscopy and intravital staining techniques are synonymous methods for the endoscopic early detection of malignant changes in the intestinal tract. Endoscopic intravital staining involves the use of absorptive stains (methylene blue and Lugol's solution), contrast stains (indigo carmine) and reactive stains (Congo red). Lugol's iodine solution is used to identify superficial carcinomas in the squamous epithelium of the oesophagus. Methylene blue stains the specialized intestinal epithelium in Barrett's oesophagus and, in addition to this, is helpful in the diagnosis of dysplasia. Intravital staining with indigo carmine contributes to contrasting and accentuating changed mucosal processes. Together with Cresyl violet, contrast staining is particularly important in detecting small, early malignant changes in the colon. The use of chromoendoscopy enables a biopsy diagnosis of superficial dysplastic changes and an accurate delineation of carcinomatous areas. In conjunction with the modern video-endoscopy (high-resolution endoscopy and magnification endoscopy), vital staining forms the diagnostic foundation for the detection of early malignant changes in the gastrointestinal tract. These techniques are therefore prerequisites to local endoscopic tumour therapy (mucosectomy). Despite their increasing acceptance, these methods must prove their diagnostic merit in randomized studies.
Coloring Agents↗
Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other Hand/Foot anomalies maps to human chromosome 3q27.
We report on a large Dutch family with a syndrome characterized by severe hand and/or foot anomalies, and hypoplasia/aplasia of the mammary gland and nipple. Less frequent findings include lacrimal-duct atresia, nail dysplasia, hypohydrosis, hypodontia, and cleft palate with or without bifid uvula. This combination of symptoms has not been reported previously, although there is overlap with the ulnar mammary syndrome (UMS) and with ectrodactyly, ectodermal dysplasia, and clefting syndrome. Allelism with UMS and other related syndromes was excluded by linkage studies with markers from the relevant chromosomal regions. A genomewide screening with polymorphic markers allowed the localization of the genetic defect to the subtelomeric region of chromosome 3q. Haplotype analysis reduced the critical region to a 3-cM interval of chromosome 3q27. This chromosomal segment has not been implicated previously in disorders with defective development of limbs and/or mammary tissue. Therefore, we propose to call this apparently new disorder "limb mammary syndrome" (LMS). The SOX2 gene at 3q27 might be considered an excellent candidate gene for LMS because the corresponding protein stimulates expression of FGF4, an important signaling molecule during limb outgrowth and development. However, no mutations were found in the SOX2 open reading frame, thus excluding its involvement in LMS.
Abnormalities, Multiple↗
Investigation of a family with autosomal dominant dilated cardiomyopathy defines a novel locus on chromosome 2q14-q22.
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the most frequent indication for heart transplantation in young patients. Probably >25% of DCM cases are of familial etiology. We report here genetic localization in a three-generation German family with 12 affected individuals with autosomal dominant familial DCM characterized by ventricular dilatation, impaired systolic function, and conduction disease. After exclusion of known DCM loci, we performed a whole-genome screen and detected linkage of DCM to chromosome 2q14-q22. Investigation of only affected individuals defines a 24-cM interval between markers D2S2224 and D2S2324; when unaffected individuals are also included, the critical region decreases to 11 cM between markers D2S2224 and D2S112, with a peak LOD score of 3.73 at recombination fraction 0 at D2S2339. The identification of an additional locus for familial autosomal dominant DCM underlines the genetic heterogeneity and may assist in the elucidation of the causes of this disease.
Adolescent↗
Panel of microsatellite markers for whole-genome scans and radiation hybrid mapping and a mouse family tree.
To facilitate whole-genome scan experiments, we selected a panel of 128 microsatellite markers on the basis of spacing and polymorphism in the strains DBA/2, BALB/c, AKR, C57BL/6, C57BL/10, A/J, C3H, 129/J, SJL/J, JF1, and PWB. Many of the primer pairs were redesigned for better performance. The last four strains were not characterized previously using these markers. JF1 and PWB are particularly interesting for intersubspecific crosses offering high polymorphism. We provide allele size data for the markers on these strains and add them to the emerging radiation hybrid framework map, which is not continuous except for chromosome 17 and 13. Information on the interrelationships of strains is useful both because of the importance of polymorphism in designing crosses and the background in assessing phenotypes. Microsatellites offer a widely dispersed, selectively neutral set of characters that lends itself conceptually to parsimony methods of analysis. The microsatellite allele size data were recoded as binary discrete characters in such a way that adjacent sizes differ by one step. Trees were generated using a Wagner parsimony method. As expected, the non-Mus domesticus strains, PWB (musculus) and JF1 (molossinus), are excluded from the domesticus strains. Among the domesticus strains, C57BL/6 and C57BL/10 (derived from the same founding pair) form a strongly supported group, as do C3H, A/J, and BALB/c (derived from the Bagg albino stock). No unique branching order for SJL/J, AKR, and DBA/2 is strongly supported, which may reflect a complicated history. Strain 129/J is clearly placed as the most deeply diverged of the domesticus strains represented.
Alleles↗
Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis.
We examined the mechanisms of interaction of crocidolite asbestos fibers with the epidermal growth factor (EGF) receptor (EGFR) and the role of the EGFR-extracellular signal-regulated kinase (ERK) signaling pathway in early-response protooncogene (c-fos/c-jun) expression and apoptosis induced by asbestos in rat pleural mesothelial (RPM) cells. Asbestos fibers, but not the nonfibrous analog riebeckite, abolished binding of EGF to the EGFR. This was not due to a direct interaction of fibers with ligand, inasmuch as binding studies using fibers and EGF in the absence of membranes showed that EGF did not adsorb to the surface of asbestos fibers. Exposure of RPM cells to asbestos caused a greater than twofold increase in steady-state message and protein levels of EGFR (P < 0.05). The tyrphostin AG-1478, which inhibits the tyrosine kinase activity of the EGFR, but not the tyrphostin A-10, which does not affect EGFR activity, significantly ameliorated asbestos-induced increases in mRNA levels of c-fos but not of c-jun. Pretreatment of RPM cells with AG-1478 significantly reduced apoptosis in cells exposed to asbestos. Our findings suggest that asbestos-induced binding to EGFR initiates signaling pathways responsible for increased expression of the protooncogene c-fos and the development of apoptosis. The ability to block asbestos-induced elevations in c-fos mRNA levels and apoptosis by small-molecule inhibitors of EGFR phosphorylation may have therapeutic implications in asbestos-related diseases.
Animals↗
Linkage of familial euthyroid goiter to the multinodular goiter-1 locus and exclusion of the candidate genes thyroglobulin, thyroperoxidase, and Na+/I- symporter.
Iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also indicate a genetic predisposition for euthyroid simple goiter. In hypothyroid goiters several molecular defects in the thyroglobulin (TG), thyroperoxidase (TPO), and Na+/I- symporter (NIS) genes have been identified. The TSH receptor with its central role for thyroid function and growth is also a strong candidate gene. Therefore, we investigated a proposita with a relapsing euthyroid goiter and her family, in which several members underwent thyroidectomy for euthyroid goiter. Sequence analysis of the complementary DNA (cDNA) of the TPO and TSH receptor genes revealed several previously reported polymorphisms. As it is not possible to exclude a functional relevance for all polymorphisms, we opted for linkage analysis with microsatellite markers to investigate whether the candidate genes are involved in the pathogenesis of euthyroid goiter. The markers for the genes TG, TPO, and NIS gave two-point and multipoint logarithm of odds score analysis scores that were negative or below 1 for all assumed recombination fractions. As no significant evidence of linkage was found, we conclude that these candidate genes can be excluded as a major cause of the euthyroid goiters in this family. In contrast, we have found evidence for linkage of familial euthyroid goiter to the recently identified locus for familial multinodular nontoxic goiter (MNG-1) on chromosome 14q. The haplotype cosegregates clearly with familial euthyroid goiter. Our results provide the first confirmation for MNG-1 as a locus for nontoxic goiter.
Adolescent↗
[Propofol for sedation in gastroscopy--a randomized comparison with midazolam].
UNLABELLED: Midazolam, a benzodiazepine with amnestic and sedative effects is the drug of choice for sedation of patients undergoing upper gastrointestinal endoscopy. Propofol, a phenolic derivate, is a short-acting anesthetic producing a more rapid onset sedation amnesia and a shorter recovery than midazolam: In higher doses it acts as hypnotic. The aim of this study was to evaluate both drugs in a prospective randomized trial for sedation of patients undergoing esophagogastroduodenoscopy (EGD). METHODS: 60 patients undergoing EGD were randomized to receive either propofol (n = 30) or midazolam (n = 30). No other analgetic or sedative drugs were used. 3 l oxygen were given routinely by nose. Blood pressure, oxygen saturation (pulse oxymetry) and heart rate was monitored continuously. The sedation quality was determined from the endoscopist and patient separately by use of a scale as either good, fair or insufficient. RESULTS: Changes of the heart rate and oxygen saturation showed no differences in both groups (> 0.05). The blood pressure decreased significant by using propofol (p < 0.01). The sedation quality was good in both groups without significant differences. The recovery time was shorter if propofol was administered (p < 0.01). CONCLUSIONS: Propofol is an alternative drug for sedation in upper endoscopy. It showed same sedation quality as midazolam with the advantage of a short recovery time. Because of a possible decrease of the blood pressure continuous monitoring is recommended.
Adult↗
[Physiotherapeutic measures on the premature-intensive care unit].
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Handling, Psychological↗
Impaired ionizing radiation-induced activation of a nuclear signal essential for phosphorylation of c-Jun by dually phosphorylated c-Jun amino-terminal kinases in ataxia telangiectasia fibroblasts.
The c-Jun amino-terminal kinases (JNKs) participate in intracellular signaling in response to cytokines and cellular stresses. JNKs are activated by phosphorylation on two critical residues, the threonine 183 and tyrosine 185, within the TPY motif. The activated JNKs, in turn, phosphorylate the nuclear protein c-Jun, a major component of the transcription factor AP1. In vitro studies have revealed a defect in ionizing radiation-induced activation of the JNK signaling pathway in lymphoblastoid cells from individuals with ataxia telangiectasia (AT). However, the biochemical basis for this signaling defect is not clear. Here, we show that ionizing radiation induces the phosphorylation of endogenous c-Jun in normal fibroblasts but not in AT fibroblasts. The p46 isoforms of dually phosphorylated JNKs were detected in the nuclei of both normal and AT fibroblasts following exposure to ionizing radiation or sham radiation. However, c-Jun kinase activity was detected in normal cells but not in AT cells. Furthermore, an exogenous purified active JNK protein was able to phosphorylate endogenous c-Jun in nuclear extracts only of normal cells and only after the cells were irradiated. Electrophoretic mobility shift assays also showed that the ionizing radiation-induced increase in the DNA binding activity of AP1 observed in normal cells was absent or markedly reduced in AT cell lines. These data suggest that the defect in ionizing radiation-induced signaling through c-Jun in AT cells is the result of impaired function of an unknown nuclear protein or proteins that negatively regulate both JNK and c-Jun.
Ataxia Telangiectasia↗
A concise synthesis and in vitro cytotoxicity of new labdane diterpenes.
A new series of labdane-related diterpenes have been synthesized from (-)-sclareol and assayed in vitro cytotoxicity against mouse and human cancer cells. A key intermediate, homodrimane and furanolabdane derivatives show good in vitro cytotoxicity comparable to those of mitomycin C and adriamycin.
Animals↗
A general mechanism for regulation of access to the translocon: competition for a membrane attachment site on ribosomes.
For proteins to enter the secretory pathway, the membrane attachment site (M-site) on ribosomes must bind cotranslationally to the Sec61 complex present in the endoplasmic reticulum membrane. The signal recognition particle (SRP) and its receptor (SR) are required for targeting, and the nascent polypeptide associated complex (NAC) prevents inappropriate targeting of nonsecretory nascent chains. In the absence of NAC, any ribosome, regardless of the polypeptide being synthesized, binds to the endoplasmic reticulum membrane, and even nonsecretory proteins are translocated across the endoplasmic reticulum membrane. By occupying the M-site, NAC prevents all ribosome binding unless a signal peptide and SRP are present. The mechanism by which SRP overcomes the NAC block is unknown. We show that signal peptide-bound SRP occupies the M-site and therefore keeps it free of NAC. To expose the M-site and permit ribosome binding, SR can pull SRP away from the M-site without prior release of SRP from the signal peptide.
Animals↗
A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-kappaB.
The signaling pathway through which ionizing radiation induces NF-kappaB activation is not fully understood. IkappaB-alpha, an inhibitory protein of NF-kappaB mediates the activation of NF-kappaB in response to various stimuli, including cytokines, mitogens, oxidants and other stresses. We have now identified an ionizing radiation-induced signaling pathway that is independent of TNF-alpha. IkappaB-alpha degradation is rapid in response to TNF-alpha induction, but it is absent in response to ionizing radiation exposure in cells from individuals with ataxia-telangiectasia (AT). Overexpression of wild-type ATM, the product of the gene defective in AT patients, restores radiation-induced degradation of IkappaB-alpha. Furthermore, phosphorylation of IkappaB-alpha by immunoprecipitated ATM kinase is increased in control fibroblasts and transfected AT cells following ionizing radiation exposure. These data provide support for a novel ionizing radiation-induced signaling pathway for activation of NF-kappaB and a molecular basis for the sensitivity of AT patients to oxidative stresses.
Acetylcysteine↗
Cloning and characterization of plastid ribosomal protein S16 gene from potato (Solanum tuberosum L. cv Désirée).
The plastid ribosomal protein s16 (rps16) gene was cloned from potato (Solanum tuberosum L. ssp. tuberosum cv Desiree) by PCR amplification to obtain a new homologous recombination site of plastid transformation. The potato rps16 genomic clone was 1627 bp in size and the coding region was interrupted by an 859 bp intron. Exon I was 40 bp, encoding 13 amino acids and exon II was 227 bp, encoding a 76 amino acid polypeptide. The nucleotide sequence of the rps16 gene from the "Désirée" potato shared perfect identity with the sequence from the "Superior" potato in the coding region. Three nucleotide substitutions, two nucleotide insertions, and one nucleotide deletion were found between the intron sequence of both "Désirée" and "Superior" cultivars. The amino acid sequence of the potato rps16 gene showed a high level of identity with rice, maize, tobacco, and mustard (84-94%) and a relatively low level compared with Bacillus stearothermophilus and E. coli (27-28%). Expression of the rps16 gene was strong in chloroplasts and transcripts were detectable in amyloplasts, suggesting that the rps16 gene is active in nonphotosynthetic plastids as well as in photosynthetic plastids. These results indicate that the potato rps16 gene can be used as a new homologous recombination site of plastid transformation for potato cultivars.
Amino Acid Sequence↗
Irreversible binding of poly(ADP)ribose polymerase cleavage product to DNA ends revealed by atomic force microscopy: possible role in apoptosis.
During apoptosis, DNA undergoes fragmentation and caspase-3 cleaves poly(ADP-ribose) polymerase (PARP) into both a 24-kDa fragment containing the DNA binding domain and an 89-kDa fragment containing the catalytic and automodification domains. Atomic force microscopy revealed that recombinant full-length PARP bound to plasmid DNA fragments and linked them into chainlike structures. Automodification of PARP in the presence of NAD+ resulted in its dissociation from the DNA fragments, which, nevertheless, remained physically aligned. A recombinant 28-kDa fragment of PARP containing the DNA binding domain but lacking the automodification domain irreversibly bound to and linked DNA fragments in the absence or presence of NAD+. Identical results were obtained on incubation of internucleosomal DNA fragments from apoptotic cells with the products of cleavage of recombinant PARP by purified caspase-3. The 24-kDa product of PARP cleavage by caspase-3 may contribute to the irreversibility of apoptosis by blocking the access of DNA repair enzymes to DNA strand breaks.
Animals↗
Stability of acetal and non acetal-type analogs of artemisinin in simulated stomach acid.
A series of non acetal-type analogs of artemisinin containing C-C bond at position-12 have been found to be 15-22 times more stable than acetal(C-O)-type prodrugs of artemisinin in simulated stomach acid.
Acetals↗
Protein extracts from the gut wall influence the postnatal development of rat myenteric neurons in vitro.
Neurons migrating from the neural crest into the presumptive gut wall need an appropriate microenvironment to survive and differentiate during ontogenesis. The rat enteric nervous system (ENS) keeps developing beyond birth. The aim of this study was to investigate the neurotrophic effects of the postnatal microenvironment. Myenteric plexus was isolated from the smooth muscle layer of newborn rats at different ages (postnatal day (p)1, p7, p14) and grown as dissociated cell cultures. The culture medium (hormone-supplemented, serum-free) was supplemented either with glial-cell-line-derived-neurotrophic factor (GDNF) or with protein extracts from homogenized smooth muscle layer of p7 rats. Cultures kept in defined medium alone were used as controls. After 18 h in vitro both GDNF and protein extract had a neuritogenic effect upon p1 and p7 neurons, while p14 neurons were only stimulated by the protein extracts. The GDNF effect upon these neurons did not differ significantly from the effects in defined medium alone. The average neurite outgrowth in extract-supplemented cultures was always longer than that seen in those treated with GDNF. Although GDNF influences the postnatal development of myentric neurons in vitro it could not be detected immunohistochemically either in Western blots of the protein extracts or in cryostat sections of the gut.
Abdominal Muscles↗