Effects of natural products containing acylresorcinol partial structures on cyclooxygenases and 5-lipoxygenase.
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Ascomycota↗
Biomedical subjects
J Krauss
Publications and source records attributed to J Krauss.
The Drosophila SHC adaptor protein is required for signaling by a subset of receptor tyrosine kinases.
Receptor tyrosine kinases (RTKs) transduce signals via cytoplasmic adaptor proteins to downstream signaling components. We have identified loss-of-function mutations in dshc, the Drosophila homolog of the mammalian adaptor protein SHC. A point mutation in the phosphotyrosine binding (PTB) domain completely abolishes DSHC function and provides in vivo evidence for the function of PTB domains. Unlike other adaptor proteins, DSHC is involved in signaling by only a subset of RTKs: dshc mutants show defects in Torso and DER but not Sevenless signaling, which is confirmed by epistasis experiments. We show by double-mutant analysis that the adaptors DOS, DRK, and DSHC act in parallel to transduce the Torso signal. Our results suggest that DSHC confers specificity to receptor signaling.
Adaptor Proteins, Signal Transducing↗
Pharmacokinetics, pharmacodynamics, and safety of microencapsulated octreotide acetate in healthy subjects.
The pharmacokinetics, pharmacodynamics, and safety of the marketed formulation of microencapsulated octreotide acetate were evaluated in an open-label study in 22 healthy cholecystectomized subjects. Each subject received a single 30 mg dose of microencapsulated octreotide acetate intramuscularly (i.m.). Concentrations of octreotide, growth hormone (GH), insulin-like growth factor binding protein 3 (IGFBP-3), and insulin-like growth factor 1 (IGF-1) as well as clinical safety were evaluated over a period of 112 days (16 weeks). After the injection, mean serum octreotide concentration initially increased rapidly, reached the maximum (Cmax, day 1 = 0.96 +/- 0.25 ng/ml) approximately 1.5 hours after dosing, and declined thereafter until 24 hours postdose (Cmin, 24 h = 0.088 +/- 0.093 ng/ml). The octreotide concentration then increased and started a sustained release from day 7 onward. Plateau concentrations were maintained through day 70 and gradually declined to below the lower limit of quantification (LLOQ) by day 112. The plateau height (Cplateau (2-112d, 60%)) was 1.68 +/- 0.88 ng/ml, and the duration (delta plateau, 60%) was 30.2 +/- 15.7 days. The integrated concentration-time curve, AUC0-112d, was 2819 +/- 782 (ng.h/ml), and the apparent half-life (t1/2) was 169 hours. To assess the variability, the drug concentrations were determined hourly for 8 hours on day 28, and the mean octreotide concentration, Cavg, day 28' was 1.55 +/- 1.26 ng/ml. The suppression of IGF-1 was statistically significant compared to the baseline (p < 0.05) through day 63; however, there were no appreciable changes in GH and IGFBP-3 concentrations after a single injection of microencapsulated octreotide acetate. Simulation of a 28-day dose schedule suggested that steady-state octreotide concentrations would be reached by the third injection with steady-state concentrations about twofold greater than the first injection. There were no serious adverse events or clinically meaningful changes in vital signs, ECGs, or laboratory evaluations observed in this study, indicating that the 30 mg i.m. dose of microencapsulated octreotide acetate was well tolerated in this population.
Abdominal Pain↗
A bispecific diabody that mediates natural killer cell cytotoxicity against xenotransplantated human Hodgkin's tumors.
CD16/CD30 bispecific monoclonal antibodies can induce remissions of Hodgkin's disease refractory to chemo- and radiotherapy. However, the development of human antimouse immunoglobulin antibodies and allergic reactions precludes repeated applications of the antibody. Moreover, problems of producing and purifying sufficient amounts of material limit the clinical practicability of this novel treatment approach. To overcome these obstacles, we have constructed a bispecific antibody in a diabody form that only employs the variable domains of the CD16/CD30 hybrid hybridoma. The diabody compared favorably with the parent CD16/CD30 bispecific antibody in its ability to activate and target natural killer cells in vitro. Its administration to mice bearing xenografted Hodgkin's lymphoma resulted in a marked regression of tumor growth, thus proving for the first time the capability of a diabody for immune recruitment in vivo. The CD16/CD30 diabody is a novel reagent that should considerably facilitate the immunotherapy of patients with refractory Hodgkin's lymphoma.
Animals↗
Surgical treatment of levodopa-induced dyskinesias.
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Antiparkinson Agents↗
Eliciting T cell immunity against poorly immunogenic tumors by immunization with dendritic cell-tumor fusion vaccines.
Dendritic cells (DCs) are the most effective APCs and are being studied as natural adjuvants or Ag delivery vehicles to elicit T cell-mediated antitumor immunity. This study examined whether inoculation of DCs fused with poorly immunogenic tumor cells elicited tumor-reactive T cells for adoptive immunotherapy. DCs derived from bone marrow of C57BL/6 (B6) mice were fused with syngeneic B16 melanoma or RMA-S lymphoma cells by polyethylene glycol. The B16/DC and RMA-S/DC fusion hybrids expressed MHC class I, class II Ags, costimulatory molecules, as well as DC-specific and tumor-derived surface markers. The tumor/DC hybrids were capable of processing and presenting tumor-derived Ags, and immunization of B6 mice with irradiated B16/DC or RMA-S/DC vaccine elicited tumor-specific CTL activities. Vaccination of B6 mice with irradiated B16/DC fusion preparations induced partial host protective immunity against B16 tumor challenge. Reduced tumor incidence and prolonged survival time were observed. Adoptive transfer of T cells derived from B16/DC vaccine-primed lymph nodes into B16 tumor-bearing mice greatly reduced the number of established pulmonary metastases with or without in vivo administration of IL-2. Moreover, adoptive transfer of RMA-S/DC vaccine-primed, cultured lymph node T cells eradicated disseminated FBL-3 tumor. The results demonstrate that tumor/DC fusion products are effective cellular vaccines for eliciting T cell-mediated antitumor immunity.
Adoptive Transfer↗
High-resolution deletion mapping of chromosome arm 17p in childhood primitive neuroectodermal tumors reveals a common chromosomal disruption within the Smith-Magenis region, an unstable region in chromosome band 17p11.2.
Loss of heterozygosity (LOH) on chromosome arm 17p is the most common genetic aberration in childhood primitive neuroectodermal tumors (PNETs). To determine the frequency and extent of 17p deletions, 29 loci on 17p were investigated in 24 tumors by using restriction fragment length polymorphism (RFLP) and microsatellite analysis. LOH on 17p was found in 9 of 24 tumors. In all tumors with LOH, a continuous stretch from the telomere to chromosome band 17p11.2 was completely deleted, and no interstitial or terminal small-scale deletions were detected in the remaining 15 tumors. In four tumors with LOH on 17p, the chromosomal breakpoint was located between D17S953 and D17S805. To identify this deletion breakpoint on the cytogenetic map of chromosome 17 and to exclude uniparental disomy, we verified our data by using fluorescence in situ hybridization (FISH) analyses. By using two yeast artificial chromosome (YAC) clones that were positive for D17S689 and D17S953, the same breakpoint was confirmed in two specimens of cerebrospinal fluid (CSF) metastases by using FISH on interphase preparations. We demonstrate that, in most childhood PNETs with LOH on 17p, the breakpoint is close to, but not within, the centromere. It varies, and it occurs predominantly between the two markers D17S689 and D17S953, which is an unstable chromosomal region that is deleted or duplicated in the Smith-Magenis syndrome. Because LOH of 17p is associated with the formation of isochromosome 17q in the majority of PNETs, this study provides entry points to determine the molecular nature of this phenomenon.
Adolescent↗
Odontogenic classification of craniopharyngiomas: a clinicopathological study of 54 cases.
Based on the striking histological similarity of craniopharyngiomas and some odontogenic tumours, we reclassified a series of 54 craniopharyngiomas (52 adamantinomatous and two papillary variants) according to the WHO classification of odontogenic tumours. Twenty-seven tumours (50%) corresponded histologically to calcifying odontogenic cyst. 13 tumours (24%) to ameloblastoma, and eight (15%) tumours showed features of both calcifying odontogenic cyst and ameloblastoma either within the same specimen or in specimens derived from different resections. Rare tumours included three cases resembling calcifying epithelial odontogenic tumour and one case resembling adenomatoid odontogenic tumour. No odontogenic counterpart could be established for papillary craniopharyngiomas. The two major subtypes, i.e. craniopharyngioma corresponding to calcifying odontogenic cyst and craniopharyngioma corresponding to ameloblastoma, did not differ in their basic clinical features. Our data confirm and extend the close histological resemblance between adamantinomatous craniopharyngioma and odontogenic tumours and cysts. Furthermore, although calcifying odontogenic cyst and ameloblastoma arising in the jaw differ in clinical presentation and outcome, our study did not reveal clinical differences for the corresponding subtypes of craniopharyngioma.
Adolescent↗
Arachnoid cysts associated with subdural hematomas and hygromas: analysis of 16 cases, long-term follow-up, and review of the literature.
OBJECTIVE: Subdural hematomas and hygromas are infrequently encountered complications of arachnoid cysts of the middle cranial fossa and are particularly rare with cysts of other regions. Reports in the literature focus on casuistic observations. Therapeutic recommendations often include fenestration or extirpation of the cyst wall, in addition to evacuation of the space-occupying lesion. This study evaluates the results of and rationale for a more conservative approach, usually without cyst removal. METHODS: Sixteen cases of complicated arachnoid cysts, from a total of 658 patients with subdural hematomas or hygromas, were analyzed retrospectively together with 75 other cases reported in the literature. Additionally, 94 magnetic resonance imaging scans from 89 patients with untreated arachnoid cysts, from a total of 11,487 examinations, were reviewed for signs of hemorrhagic complications. RESULTS: Arachnoid cysts of the middle cranial fossa were found in 2.43% of patients with chronic subdural hematomas or hygromas. This indicated a fivefold greater prevalence of arachnoid cysts, compared with our magnetic resonance imaging-examined patient group. Only two patients with untreated cysts showed signs of hemorrhage in magnetic resonance imaging scans. An excellent or good therapeutic result was achieved with evacuation of the subdural fluid by drainage or craniotomy in 13 cases and with conservative treatment in two cases. Only one patient underwent additional fenestration of the cyst wall. No additional symptoms from the arachnoid cysts occurred in a follow-up period of up to 14 years after therapy. CONCLUSIONS: We do not generally consider it necessary to perform cyst diversion or fenestration at the time of drainage of a hematoma or hygroma in previously asymptomatic arachnoid cysts.
Adolescent↗
A mutation in the D,D-carboxypeptidase penicillin-binding protein 3 of Streptococcus pneumoniae contributes to cefotaxime resistance of the laboratory mutant C604.
Cefotaxime resistance in laboratory mutant C604 of Streptococcus pneumoniae, for which the MIC is 1.5 microg/ml, is independent of alterations in high-molecular-mass penicillin-binding protein (PBP) 1a. Instead, a point mutation in PBP 3, the D,D-carboxypeptidase of this organism, caused a reduced affinity for penicillin and contributed to the decreased susceptibility. The mutation Thr-242 to Ile was located directly adjacent to the triad Lys-239-Thr-Gly, a position known to be important for beta-lactam interaction with high-molecular-mass PBPs and beta-lactamases. This mutation was absent in the PBP 3's of four genetically distinct clinical isolates resistant to high levels of penicillin. None of the pbp3 genes had a mosaic structure, but in three cases there was evidence for a site-specific recombination event within a BOX element immediately downstream of pbp3.
Bacterial Proteins↗
Mapping of chromosomal gains and losses in primitive neuroectodermal tumors by comparative genomic hybridization.
A series of 18 primitive neuroectodermal tumors (PNETs), the most common malignant central nervous system tumors of childhood, were analyzed with the recently developed approach of comparative genomic hybridization (CGH). In five cases, in which only small amounts of DNA were available, universal polymerase chain reaction was successfully applied to generate adequate probe material. In 15 tumors, chromosomal imbalances were elicited, most frequently involving chromosome 17 (loss of 17p and gain of 17q). Further recurrent imbalances included gains of the distal regions of 4p, 5p, 5q, 7q, 8q, and 9p. High-level amplifications were found on 2p24 (one case) and 8q24 (three cases), suggesting involvement of the protooncogenes MYCN and MYC, respectively. In one of these cases, Southern blot analysis could be performed, proving high-copy-number amplification of MYC. Interestingly, none of the three patients with high-copy-number amplifications of MYC responded to therapy.
Adolescent↗
Consensus: trigonocephaly.
Trigonocephaly mostly occurs in isolated synostosis of the metopic suture, but 10-20% of patients are affected by complex syndromes, and in 2-5% the condition is familial. Intracranial hypertension has been observed in a minority of cases, but is never severe. Surgery is performed mainly for cosmetic reasons, following the standard principles of craniofacial surgery. Complications are rare and satisfactory cosmetic results are generally obtained. There is little likelihood for recurrent deformity.
Craniosynostoses↗
Recurrent bacterial meningitis.
UNLABELLED: To characterize recurrent bacterial meningitis in children, we reviewed the charts of all patients treated for more than one episode of bacterial meningitis at the Würzburg University Children's Hospital from 1980 to June 1995. Twenty-five children suffered 2-13 episodes of bacterial meningitis. Most patients were referred from other hospitals to our paediatric neurosurgical service. No immunodeficiency was found. In all patients, the cause of recurrent meningitis was an anatomical lesion with 13 intracranial defects including encephaloceles, skull fractures, Mondini dysplasias, neurenteric cyst, fibrous dysplasia, persistent craniopharyngeal duct, and 12 lumboscral defects with a dermoid cyst within the lumbosacral spine. A first episode of meningitis at school age did not exclude a congenital defect. In total, 84 episodes of meningitis were treated, a pathogen was isolated in 77%. The most common pathogen was Streptococcus pneumoniae, followed by Escherichia coli, Staphylococci and others. The pathogen isolated often gave a clue to the location of the defect. Personal history was often unrewarding and in some cases the search for the anatomical lesion required repeated imaging and explorative surgery. In 24 of 25 cases, final treatment of recurrent meningitis was by surgical intervention. CONCLUSION: In recurrent bacterial meningitis, excessive diagnostic and therapeutic procedures are indicated. An anatomical defect is a very probable cause.
Algorithms↗
Penicillin-binding proteins 2x and 2b as primary PBP targets in Streptococcus pneumoniae.
Different penicillin-binding proteins PBPs are affected in cefotaxime-resistant laboratory mutants compared to piperacillin-resistant mutants. PBP2x acts as the primary PBP target in cefotaxime-resistant mutants, whereas PBP2b is the primary target in piperacillin-resistant mutants. Depending on the mutations in PBP2x, it functions as a resistance determinant for cefotaxime only, or for penicillins as well. Mutations in PBP2x of laboratory mutants are found exclusively in the penicillin-binding domain that contains three homology boxes common to all penicillin-interacting enzymes. Most mutations relevant for resistance occur close to the SXN or the KT/SG box, or at the C-terminal end of the penicillin-binding domain, similar to mutations described in PBP2b of laboratory mutants. Amino acid alterations occur at similar sites also in PBP2x of beta-lactam-resistant clinical isolates and most of these proteins also contain changes in the SXXK box with the active site serine, suggesting that these alterations may be critical for resistance development in clinical isolates.
Aminoacyltransferases↗
Resistance determinants for beta-lactam antibiotics in laboratory mutants of Streptococcus pneumoniae that are involved in genetic competence.
Laboratory mutants of Streptococcus pneumoniae resistant to either cefotaxime or piperacillin reveal defects in competence development independent of the selective beta-lactam. A resistance determinant ciaH encoding a putative histidine kinase of a two-component signal-transducing system that is also involved in competence regulation was recently identified in cefotaxime-resistant mutants. We show now that the CiaH protein can be phosphorylated by ATP in vitro, and that it also phosphorylates the cognate response regulator CiaR. The mutant C306 containing the CiaH mutation Thr-230-Pro is completely noncompetent. It does not release competence-inducing activity (competence factor) into the medium nor can such an activity be released from the cells. Competence in C306 cannot be induced upon addition of external competence factor, in contrast to the competence-defective piperacillin-resistant mutants P506 and P408. A novel resistance determinant cpoA specific for piperacillin was identified in piperacillin-resistant mutants. CpoA is responsible for the competence defect in P506 but not in P408. The results document a tight link between the action of beta-lactams and competence development in the pneumococcus and confirm that the two beta-lactams piperacillin and cefotaxime act via different primary targets.
Anti-Bacterial Agents↗
[Quality control after pelvic injuries with a scoring system].
Quality control after treatment of pelvic injuries is often poor because many criteria of assessment lack objectivity. In order to attain improved comparability of results, we present a scoring system including subjective as well as functional and radiological criteria. The assessment is based on a calculation according to the importance of the criteria. The total score supplies the final result with a breakdown into excellent, good, fair and poor. 33 patients with type B and C injuries (Tile) underwent evaluation with this scoring system. We found 15 excellent, 10 good, 2 fair and 6 poor results. The score showed that patients' most frequent handicap was pain (median 60% of maximum score). Hip mobility was hardly affected, and from the radiological point of view it appeared that alterations of pelvic symmetry and symphysis were most common. Our proposal is to apply this scoring system on a wide basis, because only with a great number of patients can the effectiveness of the score be tested and different ways of treatment assessed with regard to early and late results. Our system could be a useful contribution to sufficient quality control, particularly after such complex and severe injuries.
Activities of Daily Living↗
No preferential loss of one parental allele of chromosome 17p13.3 in childhood medulloblastoma.
Medulloblastomas are the most frequent malignant tumors of the central nervous system in childhood. Loss of heterozygosity of the telomeric part of chromosome 17p has been described frequently in these tumors, suggesting a possible second tumor-suppressor gene in this region apart from the p53 gene. Using restriction-fragment-length polymorphism and microsatellite polymorphism analysis, we screened 16 medulloblastomas for 17p13.3 deletions and compared the DNA patterns of patients' tumors and normal tissues with those of one or both parents. Loss of heterozygosity of chromosome 17p13.3 could be detected in 6 out of 16 tumors (37.5%). In 4 of these 6 tumors the maternal allele was deleted, in 2 tumors the paternal allele. Although the number of tumors investigated is limited, we find no evidence that genomic imprinting of the chromosomal region most frequently deleted in medulloblastoma plays a role in tumorigenesis.
Base Sequence↗
The role of penicillin-binding proteins in penicillin resistance of Streptococcus pneumoniae.
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Bacterial Proteins↗