Mutational changes in the p53 tumor suppressor gene are the most frequent genetic alterations in human malignant tumors. Studies have shown a correlation of p53 expression in breast cancer with tumor prognosis. In contrast to mutational activation of ras and GSP in thyroid tumors, little is known about the role of p53 in thyroid tumor development. Therefore thyroid tumors and thyroid tumor cell lines were studied for the presence of p53 mutations. Snap-frozen tissues from 57 differentiated thyroid carcinomas (DTCs) and 5 goiters were studied by immunohistochemical methods. A panel of six antibodies (pAb 240, 421, 1620, 1801, DO7, and CM1) was employed by using the ABC technique. Five cell lines from DTCs (FTC133, 236, 238, PTC337, MTC164) were examined by the same technique. Additionally, genomic DNA from the cells was amplified by the polymerase chain reaction (PCR) and the PCR product studied for p53 mutations (R273H) by mutation-specific oligonucleotide hybridization (MOH) and temperature gradient gel electrophoresis (TGGE) for the p53 exon 8. None of the benign thyroid tumors and 7 of 57 (12%) DTCs strongly express p53 with a heterogeneous distribution in the tumor tissue. All seven patients have metastatic disease or dedifferentiated tumors G3 (three of seven). CM1 was positive in two cell lines (FTC-133, PTC-337), questionable in FTC-238, and negative in FTC-236 and MTC-164. All three follicular cell lines, however, and the original tumor tissue showed the same p53 mutation (R273H) in MOH analysis and TGGE. P53 mutations are rare in thyroid tumors, but the presence of p53 mutations indicates a poor prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

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Disposition of 5-formyl- and 5-methyltetrahydrofolic acid in serum after i.v. bolus of calcium folinate: pharmacokinetic drug interaction with preadministered interferon-alpha-2b.

The influence of interferon (IFN) coadministered subcutaneously with the biomodulating agent folinic acid on the blood serum levels of 5-formyl-tetrahydrofolic acid (CHO-THFA) and the biotransformation into its main metabolite in the blood 5-methyltetrahydrofolic acid (CH3-THFA) was studied in patients receiving a chemotherapy with 5-fluorouracil. IFN causes a clear decrease of the serum concentrations of CHO-THFA and a statistically significant decrease of CH3-THFA concentrations (P < 0.01). The effect on serum concentrations could be observed in each patient, but in a different order of magnitude. As a consequence, the preadministration of IFN leads to a significant change in the basic pharmacokinetic parameters of both compounds: the mean area under the concentration-time curve is decreased at 27.4% for CHO-THFA (P < 0.025) and at 22.4% for CH3-THFA (P < 0.025), respectively. The total body clearance is elevated at 45.4% for CHO-THFA (P < 0.05) and at 23.4% for CH3-THFA (P < 0.05). The mean volume of distribution is increased by IFN at 38.2% for CHO-THFA (P < 0.025) and at 22.3% for CH3-THFA (P < 0.05). The nearly identical mean residence time in both groups indicates that CHO-THFA elimination is not affected by IFN. But the results prove a certain interaction between IFN and CHO-THFA. IFN accelerates the distribution of CHO-THFA as well as of its main metabolite from the blood into the tissue or activates the biotransformation of CHO-THFA into CH3-THFA inside the cells of the tissue. The extent of biotransformation of CHO-THFA into CH3-THFA, which takes place in the blood, is not influenced by IFN because percentage AUC-ratios CHO-THFA:CH3-THFA were 89.5:10.5% for the control group and 88.8:11.2% for the IFN group.

Aged↗

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Use of a polypectomy snare to salvage a faulted stent placement.

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Aged↗

PubMedDate not supplied

Retrovirus genomes methylated by mammalian but not bacterial methylase are non-infectious.

The biological importance of DNA methylation for gene expression in eukaryotes is becoming increasingly evident, and a direct role of methylation in gene expression has been suggested by an analysis of the infectivity of integrated retroviral genomes in a transfection assay. These studies, however, did not address whether specific methylatable residues are involved in gene regulation. Methylation by sequence-specific bacterial DNA methylases has been shown to suppress the expression of some genes, but not others. To investigate the effect of methylation on gene expression without having to rely on sequence-specific methylases, a rat liver enzyme was used to methylate in vitro all C-G dinucleotides of a proviral genomic clone. This treatment reduced the biological activity of Moloney murine leukaemia virus (M-MuLV) proviral DNA by more than three orders of magnitude, whereas complete methylation of 35 HpaII sites in the same DNA had only a marginal effect. The rat methylase-induced inactivation was reversible, as treatment of recipient cells with 5-azacytidine rendered the non-infectious viral genomes biologically active. This suggests that methylation in other C-G dinucleotides than those detectable with restriction enzymes can be crucial for gene expression.

Animals↗

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The structural gene coding for myelin-associated proteolipid protein is mutated in jimpy mice.

Mutations affecting developmental processes may allow some insight into the complexity of the biological processes involved. In mice, two mutants that affect myelin formation in the central nervous system, jimpy and shiverer, have proved to be useful models for the study of this process. The predominant proteins in myelin are the major myelin proteolipid (PLP) and the myelin basic proteins (MBP), which together account for 80-90% of total myelin proteins. It has recently been shown that the shiverer mutation is located in the MBP structural gene, but the site of the jimpy mutation, which is X-chromosome-linked and may be similar to the sex-linked dismyelinization human disease, Pelizaeus-Merzbacher disease, remains unclear. Here we provide evidence, based on a combined genetic and biochemical approach, that the sex-linked recessive mutation jimpy is located in the structural gene coding for PLP.

Animals↗

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Maternal inhibition of hepatitis B surface antigen gene expression in transgenic mice correlates with de novo methylation.

Differential modifications of the genome during gametogenesis result in a functional difference between the paternal and maternal genomes at the moment of fertilization. A possible cause of this imprinting is the methylation of DNA. The insertion of foreign DNA into transgenic mice allows the tagging of regions that are differentially methylated during gametogenesis. We describe here a transgenic mouse strain in which the expression of the hepatitis B surface antigen gene is irreversibly repressed following its passage through the female germ line. This inhibition is accompanied by the methylation of all the HpaII and HhaI sites within the foreign gene, which we have shown to be integrated into a site on chromosome 13. The irreversibility reported here contrasts with what is found with other transgenic mice sequences which are reversibly methylated after passage through the male or female germ line, though in both cases methylation appears to be important in the imprinting process.

Animals↗

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Inheritance and genetic mapping of the Campus syndrome (CPS): a high-frequency tremor disease in pigs.

A new progressive tremor disorder called Campus syndrome (CPS) was observed among the progeny of a normal boar of the Pietrain breed in Germany. Extensive backcross experiments indicate that CPS is inherited as an autosomal dominant trait, and the founder boar, Campus, is believed to be a gonadal mosaic. A linkage analysis of 57 animals mapped the CPS gene to a region on porcine chromosome 7 flanked by the markers SW1418 and SW352, which is homologous to a part of human chromosome (HSA) 14. Human dominant distal myopathy type 1 (MPD1) has been mapped to the homologous region of HSA14. As the myopathological findings in MDP1 show striking similarities to CPS, this porcine disorder may serve as an animal model for MPD1.

Animals↗

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Hypothermic blood substitution enables resuscitation after hemorrhagic shock and 2 hours of cardiac arrest.

Uncontrollable hemorrhage accounts for a large proportion of total mortality in both civilian (31%) and military (47%) trauma victims. Hypothermia is a relatively safe method that could provide total body protection during hypovolemic shock and facilitate surgical intervention as a potentially life-saving procedure. This study tested the hypothesis that profound hypothermia and complete blood replacement in an established canine model, would facilitate resuscitative therapy from exsanguinating hypovolemic shock. Adult dogs were prepared for extracorporeal bypass using closed-chest peripheral cannulation under general anesthesia. Controlled hypotensive, hemorrhagic shock (mean arterial blood pressure < 50 mmHg) was induced for 30 min at normal temperature followed by temporary resuscitation using crystalloid infusion for approximately 10 min. Using our established procedure, the dogs were then cooled externally to 27 degrees C before initiating blood substitution with Hypothermosol (Cryomedical Sciences, Inc. Rockville, MD) via the extracorporeal pump. The heart was arrested during further cooling to below 10 degrees C and Hypothermosol was recirculated for 2 hr, with (3 dogs) or without (5 dogs) 1 hr of circulatory arrest. During rewarming the animals were autotransfused, weaned from the pump, and allowed to recover. All dogs (n = 8) survived, all but one with complete neurologic recovery: blood chemistry samples examined immediately after the procedure showed significant differences (p < 0.05) in only a few parameters, including creatine kinase (CK-BB and CK-MB), compared with the previous group of control dogs. The consistent survival of dogs showing apparently normal neurologic, physiologic, and biochemical recovery supports the concept that profound hypothermia using a protective hypothermic blood substitute could provide time for therapeutic resuscitation of currently intractable trauma cases.

Animals↗

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Administration of radiographic contrast media in high-risk patients.

Patients with a prior history of an anaphylactoid reaction (AR) to radiographic contrast media (RCM) have an increased risk of an AR during subsequent RCM studies. Based on previous studies in high-risk patients using prednisone or diphenhydramine to reduce the incidence of AR, high-risk patients were treated with a combined prednisone and diphenhydramine protocol in an effort to develop an effective, practical approach to this problem. All patients with convincing histories of AR to RCM with an essential need for a repeat RCM study received 50 mg of prednisone orally every 6 hours for 3 doses ending 1 hour before the RCM study, and 50 mg of diphenhydramine intramuscularly 1 hour prior to the procedure. Resuscitation equipment was readily available. One hundred forty-seven repeat procedures using RCM were carried out in 142 high-risk patients. No serious AR occurred. Two patients had generalized urticaria that resolved in 1 hour. The overall reaction rate in these pretreated high-risk patients was 6.8%, suggesting that this prednisone-diphenhydramine program may be the preferred prophylactic regimen when repeat RCM studies are necessary.

Anaphylaxis↗

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Clinical and immunological features of patients with interleukin-5-producing T cell clones and eosinophilia.

Recent work suggests that in some patients with the hypereosinophilic syndrome, a clone of abnormal T cells produces large amounts of interleukin-5. In this study, we examined 60 patients with idiopathic eosinophilia. Sixteen patients had circulating T cells with an aberrant immunophenotype that, in most cases, were associated with different forms of skin inflammation. The abnormal T cells produced large amounts of interleukin-5, which may have increased eosinophil differentiation in the bone marrow of these patients.

Clone Cells↗

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New aspects of itch pathophysiology: component analysis of atopic itch using the 'Eppendorf Itch Questionnaire'.

Itch represents a leading symptom in dermatological practice with many psychophysiological aspects. Instruments for qualitative registration of these central nervous factors and evaluation of therapeutic measures are still missing. We analyzed in detail the subjective itch sensation in 108 patients with acute atopic eczema with a new questionnaire developed in analogy to the McGill pain questionnaire. The descriptors with the highest load in atopic itch and the most frequent reaction patterns in atopic eczema patients were identified. Itch intensity (mean VAS 62%) and eczema severity (SCORAD mean 41 points) showed a different frequency distribution pattern with a correlation of r = 0.33 (p < 0.05). Principal component analysis of the itch questionnaire data was performed and compared with the standardized SCORAD severity index for the patients with atopic eczema. Three main factors of atopic itch explained 58% of the total variance: (1) 'suffering' (correlation with SCORAD, r = 0.6); (2) 'phasic intensity' (correlation with SCORAD, r = 0.4), and (3) 'ecstatic' component (associated with certain active reaction patterns). In conclusion, the complete description of itch has to consider different factors, which may be described on a more general level by three main components. Two of these are correlated with objective criteria of disease activity.

Adolescent↗

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Human peripheral blood eosinophils express and release interleukin-8.

Eosinophils can synthesize various cytokines. We demonstrate that interleukin-8 (IL-8) mRNA and protein are constitutively expressed by freshly isolated resting human eosinophils. Most of the patients with bronchial asthma or atopic dermatitis show evidence for up-regulated IL-8 protein expression in eosinophils but not in neutrophils, suggesting that an eosinophil-specific cytokine may act in these patients. To investigate whether the intracellular IL-8 can be released, eosinophils were stimulated by different cytokines and platelet-activating factor (PAF). Priming with granulocyte/macrophage-colory-stimulating factor and a subsequent 25-min stimulation with RANTES or PAF resulted in release of IL-8 from highly purified human eosinophils in vitro.

Asthma↗

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Pharmacokinetic interaction between 4'-epidoxorubicin and the multidrug resistance reverting agent quinine.

The serum and red blood cell (RBCs) disposition of epirubicin (EPR) after intravenous bolus injection without and with coadministered quinine ( QUI) was investigated in patients undergoing a cyclic chemotherapy with EPR. QUI possesses a statistical significant influence on the EPR serum concentrations and, as a consequence, on the pharmacokinetic parameters for the initial distribution phase of EPR. Within the first 15 min after administration, EPR was distributed from the central compartment distinctly faster in compare to the control, when QUI was preadministered (t(1/2) = 6 min for the control group and t(1/2) = 3 min with QUI; -46%, p < 0.05). Yet, in the beta-phase when drug-elimination predominates, no statistical significant influence of QUI in regard to EPR serum and RBC concentrations could be observed. Half-life of elimination was 0.5 h for the control group and 8.6 h for the QUI group (-10%). The mean initial serum concentration (co) was reduced significantly by QUI from 7359 +/- 506 ng/ml to 4351 +/- 1682 ng/ml (-42%, p < 0.005). Furthermore, QUI caused a reduction of the serum bioavailability of EPR (expressed as AUC(o-24)-values) from 3404 +/- 1008 ng/ml x h to 2359 +/- 1073 ng/ml x h (-31%, p < 0.05). Vd and Vdbeta were increased at about 90% and the mean total body clearance was accelerated from 45.3 to 1487 ml/min, but due to the large standard deviations the calculated difference for these parameters was not statistically significant. In the observed time interval of 24 h, the red blood cell coefficient of distribution k(rbc) of EPR was lower if QUI was coadministered (k(rbc) = 1.25 +/- 0.12 for the control group k(rbc) = 1.15 +/- 0.13 under QUI; p < 0.04). The results point out that QUI induces an accelerated distribution of EPR from the blood into the tissue and that QUI additionally may have influence on the red-blood cell partitioning of EPR.

Antibiotics, Antineoplastic↗