What is your diagnosis? Complete avulsion of the mid-cervical portion of the trachea, with approximately 4-cm displacement of the avulsed ends.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
G Clark
Publications and source records attributed to G Clark.
Long term effects of tamoxifen. Biological effects of Tamoxifen Working Party.
A total of 153 breast cancer patients who participated in two trials of adjuvant tamoxifen and who had not recurred were recruited into a study of the long term effects of tamoxifen. There were 60 controls (no tamoxifen), 73 ex-users (mostly for 2 years) and 20 current users (median treatment duration 72 months) and the median follow-up time was 7 years. A wide ranging study of lipids, hormones, bone density and haemostasis was undertaken. When compared with controls, current users had lower cholesterol levels (especially low density cholesterol), and increased triglyceride levels. Thyroid hormones were higher and sex hormone binding globulin was almost doubled. Bone density was non-significantly higher, clotting times were slightly shorter and fibrinogen and antithrombin III levels were reduced. However few of these changes persisted in ex-users, suggesting that most of the biological effects of treatment are reversible on cessation of treatment. This is reassuring for potentially negative side-effects, but also indicates that potentially positive 'side-effects' such as cholesterol lowering only occur while on active treatment.
Bone Density↗
Measurement of gestational cocaine exposure: sensitivity of infants' hair, meconium, and urine.
We studied the sensitivity of testing the newborn infant's hair, meconium, and urine in detecting gestational cocaine exposure. The infants were born to 59 women who were interviewed to determine their use of cocaine during pregnancy and whose hair was analyzed for the presence of cocaine. Regression analysis was used to evaluate the relationship between cocaine in newborn hair and in maternal hair. Radioimmunoassay of infants' hair and gas chromatography-mass spectrometry of meconium were more sensitive than immunoassay of urine (p less than 0.02), which failed to identify 60% of cocaine-exposed infants. The quantity of benzoylecgonine in the newborn infant's hair correlated best with the proximal-segment maternal hair, representing the last 12 weeks of antepartum hair growth (R = less than R less than 0.83). Approximately half (52%) of the variation in infants' hair was explained by variation in the proximal maternal hair segment. Correlation (R = 0.77) and explained variation (59%) improved slightly when premature infants (n = 9) were excluded. We conclude that analysis of the newborn infant's hair by radioimmunoassay or of meconium by gas chromatography-mass spectrometry is more sensitive than analysis by immunoassay of urine, and can detect fetal cocaine exposure that occurred during the last two trimesters of pregnancy.
Adult↗
A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SK&F 104864) given as an intravenous bolus every 21 days.
Topotecan (SK&F 104864) is a novel antitumor agent whose mechanism of action is inhibition of the DNA unwinding protein topoisomerase I. An analog of camptothecin, topotecan was designed to be more water soluble in an effort to decrease the severe and sporadic toxicities experienced during phase I/II trials of the parent compound. In this phase I clinical and pharmacological trial, topotecan was given as a bolus intravenous (i.v.) infusion over 30 min every 21 days. A total of 42 patients entered the study, receiving doses ranging from 2.5 to 22.5 mg/m2. The maximum tolerated dose (MTD) of topotecan given in this schedule was 22.5 mg/m2. Myelosuppression, primarily neutropenia, was dose-limiting. The extent of prior therapy did not predict for more severe neutropenia. Non-hematologic toxicities were mild and included low-grade to moderate fever, nausea, vomiting, alopecia, diarrhea and skin rashes. There were no objective partial or complete responses, although there was a suggestion of antitumor activity in three patients. Topotecan undergoes pH-dependent hydrolysis of the lactone ring; only the closed, lactone form is active. The lactone form predominated during infusion, with hydrolysis occurring rapidly following the end of infusion. There were linear relationships between dose administered and peak plasma lactone concentrations as well as AUC lactone to AUC total. The lactone was rapidly cleared from plasma with a total body clearance of 25.7 (+/- 6.7) l/h/m2. The plasma lactone concentration declined rapidly with a harmonic mean terminal half-life of 3.4 (+/- 1.1)h. Lactone hydrolysis and renal excretion were the major routes of elimination.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Detecting HIV antibodies in needle-exchange syringes.
Explore the source record for details and available documents.
HIV Infections↗
Integrated approach for evaluating species and interindividual differences in responsiveness to dioxins and structural analogs.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant that is produced inadvertently during the synthesis of some organochlorine compounds, such as the chlorinated phenoxy pesticides. It is biologically and ecologically persistent, with an estimated half-life of 7 years in humans. It possesses high acute toxicity in rodents and is a carcinogen, teratogen, and immunotoxin. In chronic bioassays for carcinogenicity, TCDD at a dose of 10 ng/kg/day increases the incidence of liver tumors in female rats, making it one of the most potent animal carcinogens ever tested. A recent study in humans has shown an increase in the incidence of respiratory tract tumors in workers in chlorinated phenoxy herbicide plants. Considerable controversy and uncertainty remain, however, concerning its carcinogenic potency in humans and the reliability of using animal data to predict human risks. It is generally accepted that most, if not all, of the effects of TCDD require its binding to the Ah receptor. In addition to its toxic effects, TCDD produces a number of biochemical effects, such as induction of CYP1A1, downregulation of binding activity of the estrogen and epidermal growth factor (EGF) receptors, and changes in cytokine pathways. These effects suggest that the Ah receptor plays an important role in regulating the cell cycle. A number of structural analogs of TCDD, such as the polychlorinated dibenzofurans, also interact with the Ah receptor, and they produce the same spectrum of responses as TCDD in animal and cell models. The potency of these compounds is strongly correlated with their binding affinity to the Ah receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Sequence variation and linkage of potato U2snRNA-encoding genes established by PCR.
Plant uridylate-rich small nuclear RNA (UsnRNA)-encoding genes (UsnRNA) are present as multigene families exhibiting greater sequence variation than has been described in animal UsnRNA families. The potato U2snRNA multigene family has 25 to 40 potential gene members. Four gene variants have been analysed to date, two of which are linked. In order to investigate U2snRNA expression in potato in terms of the function of such sequence variation in development, the degree of sequence variation in both the coding region and flanking regions in this gene family must be assessed. On the assumption that at least some U2snRNA genes are linked, a polymerase chain reaction (PCR) approach, using primers designed to amplify intergenic nucleotide sequences including coding and 5' flanking regions, has been devised. Six new U2snRNA gene variant sequences and one U2snRNA pseudogene sequence have been generated. In addition, six new flanking region sequences have been produced which, in contrast to other plant UsnRNA gene families, show considerable variation in the important upstream sequence element. This PCR approach may be applicable to the analysis of genomic organisation and sequence variation of other multigene families.
Base Sequence↗
Evolutionary conservation of the spliceosomal protein, U2B''.
U1 and U2snRNPs play key roles in pre-mRNA splicing. The interactions between the U1 and U2snRNP-specific proteins, U1A, U2A' and U2B'' and their respective UsnRNAs are of interest both to elucidate their roles in splicing, and as models to study RNA-protein interactions. We have cloned a full-length cDNA, encoding U2B'', from potato. This is the first report of a sequence for a plant UsnRNP protein. The plant U2B'' sequence exhibits extensive similarity with the human U2B'' protein at both the DNA and amino acid levels. The evolutionary conservation at the protein level, particularly in sequences implicated in determining specific binding to U2snRNA, suggests conservation of U2B'' function from plants to man. The significance of amino acid substitutions in the RNP-80 motif with respect to U2snRNA binding in plants is discussed.
Amino Acid Sequence↗
The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the hepatic estrogen and glucocorticoid receptors in congenic strains of Ah responsive and Ah nonresponsive C57BL/6J mice.
The present study examines the role of the Ah receptor in the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the binding capacity of the hepatic glucocorticoid (GC) and estrogen (E) receptors in female congenic C57BL/6J mice differing only at the Ah (aromatic hydrocarbon responsiveness) locus. The Ah locus is thought to encode the Ah receptor, which regulates the effects of TCDD and related compounds on cytochrome P450IA1 and appears to mediate most of the toxic effects of TCDD. The differences between Ah responsive (Ahb/b) and nonresponsive (Ahd/d) mice appear to reflect differences in the affinity of the Ah receptor in the two strains for ligands such as TCDD. Administration of a single oral dose of TCDD (30 micrograms/kg) to Ahb/b mice produced approximately a 30% decrease in the maximum binding capacities of both the hepatic GC and E receptors, as well as 50-fold induction of a P450IA1-mediated enzymatic activity, ethoxyresorufin-O-deethylase (EROD). Tyrosine aminotransferase (TAT) activity, which is mediated by the GC receptor, was also decreased approximately 30% by TCDD. Dose-response curves indicated that Ah responsive mice are 10-fold more sensitive to induction of EROD than Ah nonresponsive mice (ED50 1.6 vs 15 micrograms/kg), as would be expected for an effect mediated by the Ah receptor. Dose-response curves also indicated that there was a statistical difference in the responsiveness of the hepatic E receptor to TCDD in the two congenic strains of mice (p less than 0.01). Surprisingly, no significant differences in the dose-response curves for the effect of TCDD on hepatic GC receptor binding or TAT activity were observed in the two strains of mice in two separate experiments. These results indicate that the Ah receptor regulates the effects of TCDD on the binding of estrogen to the hepatic estrogen receptor, but suggest that the decrease in the binding capacity of the hepatic GC receptor does not appear to be mediated directly by the Ah locus.
Animals↗
Ovarian hormones enhance 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated increases in cell proliferation and preneoplastic foci in a two-stage model for rat hepatocarcinogenesis.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent hepatocarcinogen in rodents. However, liver tumor incidence is increased by TCDD in female Sprague-Dawley rats but not male rats in chronic carcinogen bioassays. Our studies have investigated this finding by evaluating histological and biochemical parameters in a two-stage model for hepatocarcinogenesis in female Sprague-Dawley rats (intact and ovariectomized), using diethylnitrosamine (DEN) as the initiating agent and TCDD as the promoting agent. Increases in gamma-glutamyl transpeptidase-positive foci were greater in intact female rats than in ovariectomized (OVX) animals. For example, in intact rats receiving both DEN and TCDD, the percentage of liver occupied by gamma-glutamyl transpeptidase-positive foci was 0.37, compared to 0.08 in OVX rats. Values for intact or OVX rats receiving either DEN or TCDD only were 0.04 or less. Similar results were obtained when using placental glutathione S-transferase to detect hepatic preneoplastic lesions. Cell proliferation data, obtained using bromodeoxyuridine in osmotic minipumps, were consistent with preneoplastic foci data in that the hepatocyte labeling index was increased in DEN/TCDD intact rats but not in DEN/TCDD OVX rats. Analysis of data from individual animals revealed a strong correlation (P less than 0.01) between cell proliferation and placental glutathione S-transferase-positive foci/cm3 in liver. These findings did not reflect effects of ovariectomy on TCDD tissue distribution, since livers of OVX rats contained more TCDD than livers of intact rats, although both groups of rats received a dose of 1.4 micrograms TCDD/kg once every 2 weeks for 30 weeks. Hepatic cytochrome P-450d (IA2) was induced approximately 6-8-fold in all TCDD-treated groups, and the magnitude of induction was not influenced by ovariectomy. This cytochrome efficiently catalyzes metabolism of 17 beta-estradiol to catechol estrogens. Our data suggest that ovarian hormones (probably estrogen) play a significant role in the hepatocarcinogenic actions of TCDD.
Animals↗
Sequence and expression of potato U2 snRNA genes.
Plant UsnRNA multigene families show a high degree of sequence variation among individual gene members. The potato U2snRNA gene family consists of between twenty-five and forty genes. Four potato U2snRNA gene variants have been isolated. Despite the sequence variation in coding and flanking regions, all maintain the conserved U2snRNA secondary structure and all contain the plant UsnRNA promoter elements: the upstream sequence element (USE) and TATA-like box in the -70 and -30 regions respectively. In RNase A/T1 protection analyses, one of the genes, PotU2-22, protected high levels of full length U2snRNA transcripts in potato leaf, stem, root and tuber RNA. Thus, PotU2-22 or genes with identical coding regions, are highly expressed in these potato organs and therefore represent a major subset of functional U2snRNA genes. Similar expression levels of the PotU2-22 sequence variant were also found in four genetically different potato cultivars and also in tobacco, a species closely related to potato, suggesting conservation of the coding regions of expressed U2snRNA genes. A second gene, PotU2-4, protected very low levels of full length transcripts while a third gene, PotU2-11, was not expressed in the potato organs analysed. The relative expression levels of the gene variants may reflect individual gene differences in, for example, the USE and TATA regulatory elements, or variations in gene copy number.
Animals↗
Thymic peptides, stress, and depressive symptoms in older men: a comparison of different statistical techniques for small samples.
Thymic peptides play an important role in aging and immune regulation, but little is known about their relationship to psychosocial factors. One thymic fraction, thymosin-alpha 1 (TSN-alpha 1) may be of particular interest given its hypothesized role in the differentiation of immature T cells into functional, mature T cells. We examined the relationships among stress, psychological symptoms, and TSN-alpha 1 levels in two conditions; before and after a glucose challenge test. The sample consisted of 18 men, aged 48-80, participants in the Normative Aging Study. While none of the correlations reached significance in the baseline condition, life events and depressive symptoms were significantly correlated with TSN-alpha 1 in the postchallenge condition (r's = .57, and .62, respectively). Hierarchical regression analyses with cross-product interaction terms suggested that individuals who were high in both life events and depression showed the highest levels of postchallenge TSN-alpha 1, with the psychosocial variables accounting for 65% of the variance. Given the small sample size, we replicated these analyses using jackknife and bootstrap techniques, which generally confirmed these findings. Thus, these preliminary results suggest that psychosocial factors may be related to abnormal TSN-alpha 1 responses to a challenge.
Aged↗
Phase I evaluation of 773U82.HCl, a member of a new class of DNA intercalators.
The arylmethylaminopropanediols (AMAPs) are a new class of DNA intercalators. 773U82.HCl is the second of these compounds to enter clinical trial. Significant antitumor activity for 773U82.HCl was documented in a variety of murine and human tumor models. This phase I study examined a 1-, 2- and 6-hour infusion given every 28 days. Thirty-six patients received 58 courses of drug at doses ranging from 15 mg/m2 to 980 mg/m2. The dose-limiting toxicity of 773U82.HCl was hemolysis noted at 980 mg/m2. Change in color of the plasma and decreases in haptoglobin were correlated with drug concentrations of the infusate greater than or equal to 3 mg/ml. Clinically significant changes in hemoglobin levels requiring blood transfusions did not occur. Neurologic toxicity occurred at 720 mg/m2 with the most severe neurologic toxicity occurring in a patient with the highest peak plasma concentration (4.1 micrograms/ml). With an increase in duration of the infusion and amount of fluid administered, the neurologic toxicity resolved. Other toxicities included mild nausea and vomiting and a dose-related phlebitis. Pharmacokinetic studies were completed in 22 patients. The mean terminal t1/2 beta was 4.4 h with a mean apparent volume of distribution at steady state (Vdss) of 314 l/m2. The mean total body clearance was 72 l/h/m2. Peak plasma levels ranged from 0.04 to 4.14 micrograms/ml. Further studies with 773U82.HCl on this schedule at the doses studied are not recommended. Hematologic monitoring for evidence of intravascular hemolysis should be included in future studies with 773U82.HCl.
Adult↗
Using forensic techniques to verify self-reports of needle-sharing.
Explore the source record for details and available documents.
Adult↗
Evaluating needle exchange: do distributed needles come back?
We employed capture-recapture methods as a strategy for evaluating needle exchange. Needles distributed by the exchange at two time periods were marked with color coded bands indicating the date and site of distribution. Half of the marked needles (2,068/4,239) returned within two weeks of distribution, and 61 percent (2,593/4,239) returned during the study period. The rate of return for stationary exchange sites (63 percent) was greater than that for roving/mobile sites (51 percent; chi 2 = 28.6, p less than .001). Of all needles returned, 87 percent (2,248/2,593) returned to the site of original distribution.
Acquired Immunodeficiency Syndrome↗
Influence of the Ah locus on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the hepatic epidermal growth factor receptor.
The present studies examine whether the Ah receptor mediates the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the binding capacity of the hepatic epidermal growth factor (EGF) receptor in congenic strains of C57BL/6J mice that differ only at the Ah locus. The Ah locus is believed to encode the Ah receptor, which mediates the induction of cytochrome P4501A1 by TCDD and appears to mediate many of the toxic effects of TCDD. TCDD produced an 80-90% decrease in the maximum binding capacity (both high and low affinity sites) of the hepatic EGF receptor in female Ah-responsive (Ahb/b) and Ah-nonresponsive (Ahd/d) C57BL/6 mice. However, the ED50 for the effects of TCDD on the binding capacity of the EGF receptor was 10-fold higher in the Ah-nonresponsive mice, compared with the Ah-responsive mice (7 versus 0.7 micrograms/kg). TCDD did not affect the hepatic content of two EGF receptor mRNA transcripts (10 and 6 kb), indicating that the effects on the EGF receptor are not pretranslational. Similarly, TCDD did not affect the hepatic content of mRNA for transforming growth factor-alpha, an alternate ligand for the EGF receptor that is synthesized in the liver. In contrast, TCDD markedly increased the hepatic content of the mRNA for cytochrome P4501A1, which is known to be regulated transcriptionally by TCDD. The ED50 for this effect was 10-fold higher in Ah-nonresponsive mice than in Ah-responsive mice (13 versus 1.3 micrograms/kg). This study indicates that the effects of TCDD on EGF receptor ligand binding are mediated by the Ah receptor. However, unlike the effect of TCDD on cytochrome P4501A1, the effects of TCDD on the EGF receptor do not involve changes in the levels of the mRNA for this protein or changes in the mRNA for transforming growth factor-alpha, an alternate ligand for the EGF receptor.
Animals↗
Re: "Multiple births and maternal risk of breast cancer".
Explore the source record for details and available documents.
Adult↗