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At least 199 records · Page 11Linked to original sources
PubMed1997

[Does the core biopsy of solid liver lesions permit an exact histological classification? Results of a prospective study under routine clinical conditions].

PURPOSE: The aim of this prospective study was to answer the question to what extent percutaneous core-cut biopsy of solid lesions of the liver can permit (sub-)classification under routine conditions. MATERIAL AND METHODS: Subject of this study were 80 percutaneous core-cut biopsies of solid liver lesions in 75 patients. The biopsies were done consecutively under routine conditions by 10 different radiologists with Tru-Cut-needles and a biopsy gun with sonographic (n = 73) or CT (n = 7) guidance. After receiving the histological analysis, the radiologists then prospectively divided the biopsies into "valid" und "unclear" using clinical and radiologic data of the respective patient. The results were verified by a second biopsy, follow-up or surgery. RESULTS: 80% of all histological analyses were rated as "valid", 20% as "unclear". The accuracy of the "valid" reports in respect of ranking was 95% and 90% for the accurate tumour classification. These values were reduced to 81.3% and 74%, respectively, with regard to the total number of cases. The negative predictive value was reduced from 78% to 51.7%. CONCLUSION: Core-cut biopsy of solid liver lesions guided by imaging yields good results even under routine conditions as long as all histological reports have been correlated with imaging and clinical informations.

Biopsy, Needle↗
PubMed2003

Decreased cervical proinflammatory cytokines permit subsequent upper genital tract infection during pregnancy.

OBJECTIVE: The purpose of this study was to test the hypothesis that suppressed immune function in the lower genital tract, as represented by decreased concentrations of cervical proinflammatory cytokines early in pregnancy, is a risk factor for clinical chorioamnionitis. STUDY DESIGN: Interleukin-1beta, interleukin-6, and interleukin-8 were measured by enzyme-linked immunosorbent assay in cervical fluid from a cohort of 403 women at 8 to 20 weeks of gestation. RESULTS: Of the 88 women with one low cytokine concentration, 8.0% of the women had clinical chorioamnionitis compared with 4.4% among the 228 women with no low cytokines (adjusted odds ratio, 2.0; 95% CI, 0.7-5.8). Clinical chorioamnionitis occurred in 15 of the 87 women (17.2%), with two or three depressed cytokine concentrations compared with women with no low cytokines (adjusted odds ratio, 5.1; 95% CI, 2.0-13.0). CONCLUSION: Genital tract immune hyporesponsiveness, as represented by low cervical concentrations of multiple cytokines, permits subsequent clinical chorioamnionitis.

Adolescent↗
PubMed2006

Conserved markers of fetal pancreatic epithelium permit prospective isolation of islet progenitor cells by FACS.

Prospective isolation and characterization of progenitor cells is a paradigmatic strategy for studies of organ development. However, extraction of viable cells, fractionation of lineages, and in vitro analysis of progenitors from the fetal pancreas in experimental organisms like mice has proved challenging and has not yet been reported for human fetal pancreas. Here, we report isolation of pancreatic islet progenitor cells from fetal mice by FACS. Monoclonal antibodies that recognize cell-surface proteins on candidate stem cells in brain, skin, and other organs enabled separation of major pancreatic cell lineages and isolation of native pancreatic cells expressing neurogenin 3, an established marker of islet progenitors. New in vitro cell culture methods permitted isolated mouse islet progenitors to develop into hormone-expressing endocrine cells. Insulin-producing cells derived in vitro required or expressed factors that regulate fetal beta cell differentiation; thus, the genetic programs normally controlling in vivo mouse islet development are similarly required in our system. Moreover, antibodies that recognize conserved orthologous cell-surface epitopes in human fetal pancreas allowed FACS-based enrichment of candidate islet progenitor cells expressing neurogenin 3. Our studies reveal previously undescribed strategies for prospective purification and analysis of pancreatic endocrine progenitor cells that should accelerate studies of islet development and replacement.

AC133 Antigen↗
PubMed1969

A mutant of Escherichia coli permitting replication of two F factors.

Control mechanisms of replication of bacterial genetic elements are poorly understood at present. We have studied one such mechanism involving replication of the F factor in Escherichia coli. The F factor can replicate either autonomously in F(+) or F' strains, or as an integral part of the chromosome in Hfr strains. We have shown that presence of either an integrated F factor or a free F factor prevents replication of a second free F factor. Two integrated F factors can replicate in the same cell. The present experiments show that when a F'lac element was transferred by mating into an Hfr strain, it had to become integrated into the chromosome in order to persist. With a recombination-deficient (recA) Hfr strain as recipient, the frequency of F'lac integration was greatly reduced. This permitted us to isolate a mutant Hfr strain in which the F'lac element was able to replicate autonomously. The mutation has most likely occurred in the integrated F factor itself. Availability of this new recA mutant Hfr strain facilitates genetic analysis of the F factor, since in recA(+) Hfr strains frequent integration of a free F factor into the chromosome obscures recognition of complementation and recombination between two free F factors.

Chromosomes, Bacterial↗
PubMed1981

Reduction of K+ efflux in cultured mouse fibroblasts, by mutation or by diuretics, permits growth in K+-deficient medium.

The mouse fibroblastic cell line LM(TK-) is unable to grow at external K+ concentrations below a threshold value of 0.4 mM. At subthreshold K+ concentrations, LM(TK-) cells rapidly lose intracellular K+ and eventually lyse. We have analyzed the pathway primarily responsible for K+ efflux under these experimental conditions and reports its specific inhibition by two diuretics, furosemide and bumetanide. Bumetanide, an analog of furosemide, was a more potent inhibitor (by several orders of magnitude) than was furosemide itself. The effects of ouabain and bumetanide were additive, suggesting independence of diuretic-sensitive K+ efflux from Na+/K+ pump-mediated fluxes. Characterization of K+ efflux in LTK-5, a mutant derived from LM(TK-) and selected for its ability to grow at 0.2 mM K+ indicated that the mutant had lost the diuretic-sensitive K+ efflux pathway. Net cation fluxes, steady-state intracellular cation concentrations, and growth at reduced K+ concentrations were comparable for LM(TK-) cells maximally inhibited by diuretics and for the LTK-5 mutant grown either in the presence or absence of diuretics. Thus, reduction in K+ efflux, either by diuretic addition diuretics. Thus, reduction in K+ efflux, either by diuretic addition or by genetic alteration, can permit the cell to maintain normal cation gradients and to grow at otherwise subthreshold external K+ concentrations.

Animals↗
PubMed1994

A net +1 frameshift permits synthesis of thymidine kinase from a drug-resistant herpes simplex virus mutant.

Clinical resistance to antiviral drugs requires that a virus evade drug therapy yet retain pathogenicity. Thymidine kinase (TK)-negative mutants of herpes simplex virus are resistant to the drug, acyclovir, but are attenuated for pathogenicity in animal models. However, numerous cases of clinical resistance to acyclovir have been associated with viruses that were reported to express no TK activity. We studied an acyclovir-resistant clinical mutant that contains a single-base insertion in its tk gene, predicting the synthesis of a truncated TK polypeptide with no TK activity. Nevertheless, the mutant retained some TK activity and the ability to reactivate from latent infections of mouse trigeminal ganglia. The mutant expressed both the predicted truncated polypeptide and a low level of a polypeptide that comigrated with full-length TK on polyacrylamide gels and reacted with anti-TK antiserum, providing evidence for a frameshifting mechanism. In vitro transcription and translation of mutant tk genes, including constructs in which reporter epitopes could be expressed only if frameshifting occurred, also gave rise to truncated and full-length polypeptides. Reverse transcriptase-polymerase chain reaction analysis coupled with open reading frame cloning failed to detect alterations in tk transcripts that could account for the synthesis of full-length polypeptide. Thus, synthesis of full-length TK was due to an unusual net +1 frameshift during translation, a phenomenon hitherto confined in eukaryotic cells to certain RNA viruses and retrotransposons. Utilization of cellular frameshifting mechanisms may permit an otherwise TK-negative virus to exhibit clinical acyclovir resistance.

Acyclovir↗
PubMed1994

Reduced Rho-dependent transcription termination permits NusA-independent growth of Escherichia coli.

NusA and Rho are essential Escherichia coli proteins that influence transcription elongation and termination. We show that an E. coli derivative unable to express NusA, because its sole nusA gene contains a large deletion/substitution, is viable providing that the bacterium also carries a rho mutation that reduces transcription termination. This Rho-mediated suppression is not allele specific, since either a mutation changing amino acid 134 [rho(E134D)] or a mutation changing amino acid 352 (rho1) allows growth of a nusA-deleted E. coli. However, both rho mutations similarly decrease transcription termination 8- to 9-fold. We propose that the essential role of NusA is to enhance pausing of RNA polymerase at certain sites, permitting tight coupling of transcription and translation. This coupling interferes with Rho access to and/or movement on the nascent RNA and blocks premature termination of transcription. Thus, NusA-dependent coupling should be less important in a mutant with low Rho activity. The fact that E. coli grows without NusA argues that NusA should be considered an accessory factor rather than a subunit of RNA polymerase.

Alleles↗
PubMed2001

Conjugation of folate via gelonin carbohydrate residues retains ribosomal-inactivating properties of the toxin and permits targeting to folate receptor positive cells.

Conjugation of folate to proteins permits receptor-mediated endocytosis via the folate receptor (FR) and delivery of the conjugate into the cytoplasm of cells. Since many cancers up-regulate the FR it has enabled the targeting of toxins to tumor cells resulting in specific cell death. However, current conjugation methods rely on chemistries that can affect certain catalytic subunits, such as the A-chain of the plant toxin gelonin. As a result many folate-targeted toxins are a compromise between receptor/ligand interaction and toxin activity. We describe the first example of folate conjugated to a protein via carbohydrate residues, using a novel SH-folate intermediate. The folate-gelonin conjugate retains over 99% of toxin activity in a cell-free translational assay compared with unmodified gelonin and is able to bind the FR at the same affinity as free folic acid (10(-10) m). Additionally, the conjugate exhibits prolonged inhibition of protein synthesis in FR positive cell lines in vitro. Folate linked to gelonin via amino conjugation exhibits the same affinity for FR as free folic acid but the toxin is 225-fold less active in a cell-free translational assay. The effect of different conjugation methods on toxin activity and the implications for folate targeting of other glycoproteins are discussed.

Binding, Competitive↗
PubMedDate not supplied

The identification of Combretum gums which are not permitted food additives, II.

Combretum gums, readily available at low prices in East and West Africa, may be offered for sale as 'gum arabic'. Vigilance is necessary to detect such misrepresentations because Combretum gums differ greatly from gum arabic (Acacia senegal (L.) Willd.) in terms of quality, solution properties and value. Moreover, because there is no toxicological evidence for their safety in use, Combretum gums are not included in any of the international lists of permitted food additives. Food manufacturers and regulatory authorities therefore require data that characterize Combretum gums so that their use in foodstuffs can be prevented. This paper presents such data for the gums from a further six Combretum species. All of these have negative optical rotations similar to that of food grade gum arabic. It is no longer sufficient, therefore, to rely solely on an optical rotation measurement to confirm the identity of gum arabic. The additional analyses necessary to differentiate between Combretum gums and gum arabic are discussed.

Amino Acids↗
PubMed2004

A second heavy chain permits survival of high affinity autoreactive B cells.

Anti-DNA antibody is the serological hallmark of systemic lupus erythematosus (SLE). While antibodies with this specificity may be generated in many individuals, only patients with SLE fail to regulate them effectively. We have demonstrated previously that in non-autoimmune mice transgenic for the heavy chain of the R4A-gamma2b anti-DNA antibody, the existence of high affinity, IgG2b dsDNA binding B cells is tightly correlated with the co-expression of endogenous IgM heavy chain. These cells are anergic. In contrast, low affinity IgG2b dsDNA binding B cells do not express an endogenous heavy chain and represent a population of immunocompetent autoreactive B cells. In order to determine whether the presence of a second heavy chain permits the high affinity autoreactive B cells to escape deletion, the R4A-gamma2b mouse was mated to a strain with a targeted deletion of the transmembrane portion of the mu heavy chain, muMT mice, to produce R4A-gamma2b/muKO mice. Serum titers of anti-DNA antibodies were negligible in both R4A-gamma2b and R4A-gamma2b/muKO mice. In R4A-gamma2b/muKO mice, however, LPS was able to activate a DNA-reactive population although an LPS inducible DNA-reactive population. Light chain gene usage in transgene expressing B cells from R4A-gamma2b/muKO mice was similar to that of the previously defined low affinity anti-DNA B cells that escape tolerance. These data suggest a requirement for a second heavy chain for the survival of this anergic B cell subset.

Amino Acid Sequence↗
PubMed2000

Case history review--demilitarization combustion permits.

In May 1993, Administrative Browner of the U.S. Environmental Protection Agency (USEPA) announced that an indirect exposure health risk assessment was required for all hazardous waste combustion facilities seeking a Resource Conservation and Recovery Act permit. These types of risk assessments evaluate the health and environmental effects from inhalation of emissions (direct exposure) and from contact with environmental media and consumption of food products impacted by the emissions (indirect exposure). Completion of an indirect exposure risk assessment is often complicated by the various methodologies available for generating results and by the requirements of the regulating community. To minimize this complexity and to maximize consistency between risk assessments, the USEPA developed a number of detailed guidance documents. Site-specific conditions and toxicological data gaps, however, continue to present challenges not addressed by these guidance documents. This paper presents some of the specific challenges encountered by the U.S. Army Center for Health Promotion and Preventive Medicine when performing indirect exposure health risk assessments for several demilitarization combustion facilities.

Chemical Warfare Agents↗
PubMed1985

Multiple cancers. Tumor burden permits the outgrowth of other cancers.

We demonstrate that tumor-bearing hosts permit the outgrowth of "potentially malignant" cells that are located at a different site. These second cancers continued to grow and kill their hosts even though they retain the "premalignant" phenotype, even after removal of the original malignancy. The potentially malignant cells used in these experiments were ultraviolet light- or methylcholanthrene-induced regressor tumor cells that are rejected regularly by normal mice at any testable dose, and only form progressive tumors in immunosuppressed individuals. The immunological rejection of these highly immunogenic, potentially malignant cells was suppressed by Thy-1+, Ly-2-, nonadherent, radio-sensitive suppressor cells in the tumor-bearing mice. These suppressor cells were absent in nude tumor-bearing mice. Unlike helper and cytolytic T cell-mediated responses, which are exquisitely tumor specific, the suppression caused by a progressively growing tumor was crossreactive among many syngeneic, independently derived tumors induced by different carcinogens. However, T cell-mediated immune responses to alloantigens, allogeneic tumors, certain syngeneic tumors, and humoral responses to xenogeneic red blood cells were normal in these mice. The immune suppression in the tumor-bearing animals closely simulated that induced by ultraviolet light irradiation, and both types of suppression might therefore share common mechanisms. Our findings may contribute to understanding the growth, development, and possible control of multicentric malignancies and add a precaution to the potential use of strongly immunogenic tumor variants for active immunotherapy in hosts bearing less immunogenic tumors.

Animals↗
PubMed1990

In vivo administration of interleukin 2 plus T cell-depleted syngeneic marrow prevents graft-versus-host disease mortality and permits alloengraftment.

Previous work from this laboratory has demonstrated that T cell-depleted (TCD) syngeneic marrow can delay, but not prevent, the mortality from acute graft-vs.-host disease (GVHD) caused by MHC-mismatched lymphoid cells administered to lethally irradiated mice. We demonstrate here that a protective effect against GVHD is also observed after in vivo treatment with IL-2. Administration of 10,000-50,000 U of IL-2 twice daily for the first 5 d after bone marrow transplantation markedly reduced the mortality from both acute and chronic GVHD induced across complete MHC barriers in lethally irradiated mice, and frequently led to long-term survival. Complete allogeneic reconstitution was demonstrated in all long-term survivors of this treatment regimen. While either IL-2 or TCD syngeneic marrow administered alone was protective in some experiments, the maximal protective effect was observed after administration of both IL-2 and TCD syngeneic marrow, especially when the effects of IL-2 were suboptimal. The timing of IL-2 administration was critical to this beneficial effect, since a delay of 7 d in commencing IL-2 treatment was associated with accelerated GVHD mortality. This new approach to the prevention of GVHD permits the administration of allogeneic T cells, and may therefore avoid the increased incidence of graft failure and loss of antileukemic effects associated with the T cell depletion of allogeneic marrow, which is otherwise required for the prevention of GVHD.

Animals↗
PubMed1998

Transgene expression of bcl-xL permits anti-immunoglobulin (Ig)-induced proliferation in xid B cells.

Mutations in the tyrosine kinase, Btk, result in a mild immunodeficiency in mice (xid). While B lymphocytes from xid mice do not proliferate to anti-immunoglobulin (Ig), we show here induction of the complete complement of cell cycle regulatory molecules, though the level of induction is about half that detected in normal B cells. Cell cycle analysis reveals that anti-Ig stimulated xid B cells enter S phase, but fail to complete the cell cycle, exhibiting a high rate of apoptosis. This correlated with a decreased ability to induce the anti-apoptosis regulatory protein, Bcl-xL. Ectopic expression of Bcl-xL in xid B cells permitted anti-Ig induced cell cycle progression demonstrating dual requirements for induction of anti-apoptotic proteins plus cell cycle regulatory proteins during antigen receptor mediated proliferation. Furthermore, our results link one of the immunodeficient traits caused by mutant Btk with the failure to properly regulate Bcl-xL.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2000

Premature expression of T cell receptor (TCR)alphabeta suppresses TCRgammadelta gene rearrangement but permits development of gammadelta lineage T cells.

The T cell receptor (TCR)gammadelta and the pre-TCR promote survival and maturation of early thymocyte precursors. Whether these receptors also influence gammadelta versus alphabeta lineage determination is less clear. We show here that TCRgammadelta gene rearrangements are suppressed in TCRalphabeta transgenic mice when the TCRalphabeta is expressed early in T cell development. This situation offers the opportunity to examine the outcome of gammadelta versus alphabeta T lineage commitment when only the TCRalphabeta is expressed. We find that precursor thymocytes expressing TCRalphabeta not only mature in the alphabeta pathway as expected, but also as CD4(-)CD8(-) T cells with properties of gammadelta lineage cells. In TCRalphabeta transgenic mice, in which the transgenic receptor is expressed relatively late, TCRgammadelta rearrangements occur normally such that TCRalphabeta(+)CD4(-)CD8(-) cells co-express TCRgammadelta. The results support the notion that TCRalphabeta can substitute for TCRgammadelta to permit a gammadelta lineage choice and maturation in the gammadelta lineage. The findings could fit a model in which lineage commitment is determined before or independent of TCR gene rearrangement. However, these results could be compatible with a model in which distinct signals bias lineage choice and these signaling differences are not absolute or intrinsic to the specific TCR structure.

Animals↗
PubMed1995

HIV type 1 intraperitoneal infection of rabbits permits early detection of serum antibodies to Gag, Pol, and Env proteins, neutralizing antibodies, and proviral DNA from peripheral blood mononuclear cells.

The aim of this study is the development of an animal model useful for studying HIV-1 pathogenesis, candidate vaccines, and antiviral drugs. Aseptic thioglycolate peritonitis was induced in six rabbits. After 4 days, four rabbits were infected with 1 ml of HIV-1 stock containing 100 times the MID50. Blood samples were collected every 2 weeks for 8 months. Serum antibodies were tested by ELISA, using as antigen the recombinant protein p24; synthetic peptides of highly conserved regions of p31, gp41, and gp120; and a synthetic peptide of gp120 at the V3 loop region of HIV-1 strains IIIB and MN. Furthermore, neutralizing antibodies were tested by a microscale neutralization assay. Proviral DNA was detected by PCR, and virus isolation was performed by a cocultivation technique using primary rabbit peripheral blood mononuclear cells (PBMCs). All infected rabbits produced antibodies to HIV-1 proteins within 2 weeks and up to 8 months after virus infection. Serum antibodies were directed against the Env (gp120 and gp41), Gag (p24), and Pol (p31) proteins and against two synthetic peptides whose sequence corresponds to gp120 at the V3 loop region of HIV-1 strains IIIB and MN. Neutralizing antibodies were also detected in the sera of infected animals. Proviral DNA was detected in PBMCs by PCR within 4 weeks and up to 8 months after HIV-1 infection. HIV-1 was also isolated from PBMCs of infected animals at 30, 60, and 120 days after infection. Results obtained indicate that HIV-1 intraperitoneal infection of the rabbit permits the early detection of serum antibodies to Gag, Pol, and Env proteins, neutralizing antibodies, and proviral DNA sequences from PBMCs.

Animals↗
PubMed2006

Adenovirus-mediated and targeted expression of the sodium-iodide symporter permits in vivo radioiodide imaging and therapy of pancreatic tumors.

Pancreatic cancer is the fourth leading cause of cancer death in the United States. It is highly aggressive with no uniformly effective chemotherapy available for metastatic disease. The sodium-iodide symporter (NIS) is a transmembrane protein responsible for uptake of iodide into cells. The presence of NIS in thyroid cells permits diagnostic imaging and therapy of thyroid tumors, using radioiodide. Previous studies from this laboratory reported mucin-1 (MUC1)-driven expression of NIS in cancer cells. MUC1 overexpression has also been reported in 90% of pancreatic tumors. In this study Ad5/MUC1/NIS was used to infect pancreatic cancer cells both in vitro and in vivo, to investigate the potential for radioiodide imaging and ablation of this disease. In vitro studies revealed a 43-fold increase in iodide uptake in NIS-transduced cells compared with controls. In vivo imaging revealed effective iodide uptake and retention at the site of NIS-transduced tumors, with optimal uptake (13% of injected dose) observed 5 hr after iodide administration. Intravenous delivery was performed to investigate potential hepatotoxicity of the construct in the event of virus leakage. Intravenous injection of Ad5/CMV/NIS resulted in robust iodide uptake throughout mouse liver, whereas no uptake was detected in the liver of animals given Ad5/MUC1/NIS intravenously. Administration of therapeutic doses of 131I resulted in significant regression of NIS-transduced tumors, with a mean 50% reduction in volume within 10 weeks of therapy (p<0.0001). The ability to target NIS expression to pancreatic cancer, which has such limited treatment options, may be highly beneficial and warrants further investigation.

Adenoviridae↗
PubMed1989

Stable, resealable pores formed in sea urchin eggs by electric discharge (electroporation) permit substrate loading for assay of enzymes in vivo.

We describe a simple electroporation procedure for loading suspensions of unfertilized sea urchin eggs with impermeant small molecules under conditions that allow close to 90% successful fertilization and development. Poration is carried out in a low-Ca2+ medium that mimicks the intracellular milieu. The induced pores remain open for several minutes in this medium, allowing loading of the cells; resealing is achieved by adding back millimolar calcium ions to the medium. While the pores are open, an influx of exogenous molecules and efflux of endogenous metabolites takes place, and the eggs can lose up to 40% of their ATP content and still survive. Introduced metabolites are utilized by the cells, e.g., introduced 3H-thymidine is incorporated into DNA. This procedure will be useful for loading impermeant substrates into eggs, permitting in vivo assessment of metabolism, and also for introducing other interesting impermeant molecules, such as inhibitors, fluorescent indicators, etc. Though the details may differ, the principle of electroporation in an intracellular-like medium may prove to be useful for loading other cell types with minimal loss of viability.

Adenosine Triphosphate↗