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Addition of crude coal tar to the standard therapy in Cologne since 1937 - dithranol and salicylic acid in white petrolatum - reveals less cutaneous irritation; the duration of therapy is shortened.
Five normal adult volunteers without cutaneous disease applied 2% crude coal tar to the skin for eight-hour periods on two consecutive days. Blood extracts subjected to gas chromatography and mass spectrometry yielded evidence of absorption in all five volunteers. Phenanthrene, anthracene, pyrene, and fluoranthene, found in four of our volunteers, have been shown to be tumor initiators or cocarcinogens.
As shown in bilateral comparison studies addition of crude coal tar (T) to standard antipsoriatic therapy with dithranol and salicylic acid in white petrolatum (CVS) diminished the dithranol-irritation; consequently, accelerated application of increasing dithranol-concentrations shortened the duration of TCSV -therapy.
Pityriasis Alba, a dermatosis whose significance is basically cosmetic, is extremely common and so benign that the majority of patients-dark skinned children and young people do not consult a physician. Nevertheless due to its high incidence and chronicity a large number of patients eventually seek relief. The various treatments currently employed based on a mistaken concept of its etiology are ineffective, though the dermatosis disappears spontaneously after some time. The use of cream containing 2% coal tar., 1% diiodohydroxyquinolin and 0.5% hydrocortisone applied 3 times a day for one month on 29 patients in a double blind trial compared with on the contralateral region, proved to have acceptable results, with a highly significant difference compared with the placebo (P less than 0,0005).
Tobaccos from countries with high and low incidences of lung cancer were analyzed. Tobacco concentrations of polonium-210 were similar in cigarettes from high- and low-incidence countries, as were levels of cigarette smoke tar and nicotine. Tobaccos from low-incidence countries had significantly lower Alternaria spore counts. Mean selenium concentrations of tobaccos from the high-incidence countries (0.16 +/- 0.05 micrograms/g) were significantly lower than those of tobaccos from the low-incidence countries (0.49 +/- 0.22 micrograms/g).
Coal tar-treated psoriasis patients were used as a model population to test a newly developed enzyme-linked immunosorbent assay (ELISA) for urinary excretion of benzo(a)pyrene and related polycyclic aromatic hydrocarbons (PAHs). The ability of the ELISA to detect exposure was also compared with that of two previously established biomonitoring methods, measurement of urinary 1-hydroxypyrene by high performance liquid chromatography with fluorescence detection and mutagenicity measured by the Salmonella typhimurium mutagenesis assay. Urine samples were collected from 57 patients and 53 untreated volunteers. Urinary excretion of PAH metabolites, measured by competitive ELISA with a monoclonal antibody (4D5), was elevated in patients (mean, 730 +/- 1370 mumol/mol creatinine) compared with untreated volunteers (110 +/- 90 mumol/mol creatinine; P < 0.0001). 1-Hydroxypyrene also was elevated in patients (mean, 547 +/- 928 mumol/mol creatinine) compared with volunteers (mean, 0.14 +/- 0.17 mumol/mol creatinine; P < 0.0001). Much larger differences between mean values in patients and volunteers were observed with the 1-hydroxypyrene assay compared with the PAH metabolite ELISA. No significant effect of smoking could be detected by either assay. Analysis by the Salmonella typhimurium mutagenesis assay indicated elevated mutagenicity in urine from patients (1410 +/- 2750 revertants/mmol creatinine) compared with volunteers (715 +/- 846 revertants/mmol creatinine; P = 0.072). In all subjects, there was a good correlation between the PAH metabolites and both 1-hydroxypyrene (r = 0.717; P < 0.0001) and urinary mutagenicity (r = 0.317; P = 0.004). These results suggest that the ELISA, which easily can be carried out on large numbers of samples, can be used for monitoring urinary excretion of PAHs in a high exposure population. Ongoing studies are designed to determine its applicability to lower exposure populations.
A group of eczema patients topically treated with coal tar (CT) ointments was used as a model population to examine the applicability of DNA adducts in WBC subpopulations as a measure of dermal exposure to polycyclic aromatic hydrocarbons (PAHs). Aromatic DNA adducts were examined by 32P-postlabeling in exposed skin and WBC subsets, and urinary excretion of PAH metabolites was determined to assess the whole-body burden. The median urinary excretion of 1-hydroxypyrene and 3-hydroxybenzo(a)pyrene was 0.39 (range, 0.12-1.57 micromol/mol creatinine) and 0.01 micromol/mol creatinine (range, <0.01-0.04 micromol/mol creatinine), respectively, before the dermal application of CT ointments. After treatment for 1 week, these levels increased to 139.7 (range, 26.0-510.5 micromol/mol creatinine) and 1.18 micromol/mol creatinine (range, <0.01-2.14 micromol/mol creatinine), respectively, indicating that considerable amounts of PAHs were absorbed. Median aromatic DNA adduct levels were significantly increased in skin from 2.9 adducts/10(8) nucleotides (nt; range, 0.7-10.0 adducts/10(8) nt) before treatment to 63.3 adducts/10(8) nt (range, 10.9-276.2 adducts/10(8) nt) after treatment with CT, in monocytes from 0.28 (range, 0.25-0.81 adducts/10(8) nt) to 0.86 adducts/10(8) nt (range, 0.56-1.90 adducts/10(8) nt), in lymphocytes from 0.33 (range, 0.25-0.89 adducts/10(8) nt) to 0.89 adducts/10(8) nt (range, 0.25-3.01 adducts/10(8) nt), and in granulocytes from 0.28 (range, 0.25-0.67 adducts/10(8) nt) to 0.54 adducts/10(8) nt (range, 0.25-1.58 adducts/10(8) nt). A week after stopping the CT treatment, the DNA adduct levels in monocytes and granulocytes were reduced to 0.38 (range, 0.25-0.71 adducts/10(8) nt) and 0.38 adducts/10(8) nt (range, 0.25-1.01 adducts/10(8) nt), respectively, whereas the adduct levels in lymphocytes remained enhanced [1.59 adducts/10(8) nt (range, 0.25-2.40 adducts/10(8) nt)]. Although the adduct profiles in skin and WBC subsets were not identical, and the adduct levels in WBCs were significantly lower as compared with those in skin, the total DNA adduct levels in skin correlated significantly with the adduct levels in monocytes and lymphocytes, but not with those in granulocytes. Excretion of urinary metabolites during the first week of treatment was correlated with the percentage of the skin surface treated with CT ointment and decreased to background levels within a week after the cessation of treatment. 3-Hydroxybenzo(a)pyrene excretion, but not that of 1-hydroxypyrene, correlated significantly with the levels of DNA adducts in skin that comigrated with benzo(a)pyrene-diol-epoxide-DNA. This study indicates that the DNA adduct levels in mononuclear WBCs can possibly be used as a surrogate for skin DNA after dermal exposure to PAHs.
Guinea pigs were injected with coal tar (CT) (intratracheally, 25 mg per animal once a week or a month for 2 or 8 months, respectively), then they were infected with MBT (H37Rv, 0.1 mg, subcutaneously). There were changes in hematological responses to MBT changes (in the context of the cell composition of bone marrow and peripheral blood), their pattern was associated with the mode of exposure to CT preceding MBT inoculation. The greatest differences were found in the responses of bone marrow lymphopoiesis and peripheral lymphocytes upon both exposures to CT. On greater exposure to CT (once a week) the changes in the blood system indicated that CT had an adverse effect on the course of experimental tuberculosis, while on lesser exposure (once a month), the effect of CT was more favourable.
CONTEXT: Wound botulism (WB) is a potentially lethal, descending, flaccid, paralysis that results when spores of Clostridium botulinum germinate in a wound and elaborate neurotoxin. Since 1988, California has experienced a dramatic increase in WB associated with injecting "black tar" heroin (BTH), a dark, tarry form of the drug. OBJECTIVE: To identify risk factors for WB among injecting drug users (IDUs). DESIGN: Case-control study based on data from in-person and telephone interviews. PARTICIPANTS: Case patients (n=26) were IDUs who developed WB from January 1994 through February 1996. Controls (n=110) were IDUs newly enrolled in methadone detoxification programs in 4 counties. MAIN OUTCOME MEASURES: Factors associated with the development of WB. RESULTS: Among the 26 patients, the median age was 41.5 years, 15 (58%) were women, 14 (54%) were non-Hispanic white, 11 (42%) were Hispanic, and none were positive for the human immunodeficiency virus. Nearly all participants (96% of patients and 97% of controls) injected BTH, and the mean cumulative dose of BTH used per month was similar for patients and controls (27 g and 31 g, respectively; P=.6). Patients were more likely than controls to inject drugs subcutaneously or intramuscularly (92% vs 44%, P<.001) and used this route of drug administration more times per month (mean, 67 vs 24, P<.001), with a greater cumulative monthly dose of BTH (22.3 g vs 6.3 g, P<.001). A dose-response relationship was observed between the monthly cumulative dose of BTH injected subcutaneously or intramuscularly and the development of WB (chi2 for linear trend, 26.5; P<.001). In the final regression model, subcutaneous or intramuscular injection of BTH was the only behavior associated with WB among IDUs (odds ratio, 13.7; 95% confidence interval, 3.0-63.0). The risk for development of WB was not affected by cleaning the skin, cleaning injection paraphernalia, or sharing needles. CONCLUSIONS: Injection of BTH intramuscularly or subcutaneously is the primary risk factor for the development of WB. Physicians in the western United States, where BTH is widely used, should be aware of the potential for WB to occur among IDUs.
We report on an infant with the syndrome of Thrombocytopenia with Absent Radii (TAR) with severe lower-limb involvement. Amegakaryocytic thrombocytopenia was detected at 6 days when the platelet count was 11,000/microL. The platelet count increased steadily to 100,000/microL at 3 years. The patient required bilateral above-knee amputations for femorotibial synostoses. We recommend postponement of all elective operations until platelet counts are normal.
The architecture of the human immunodeficiency virus type 1 (HIV-1) genome presents an intriguing dilemma for the 3' processing of viral transcripts--to disregard a canonical 'core' poly(A) site processing signal present at the 5' end of the transcript and yet to utilize efficiently an identical signal that resides at the 3' end of the message. The choice of processing sites in HIV-1 appears to be influenced by two factors: (i) proximity to the cap site, and (ii) sequences upstream of the core poly(A) site. We now demonstrate that an in vivo-defined upstream element that resides within the U3 region, 76 nucleotides upstream of the AAUAAA hexamer, acts specifically to enhance 3' processing at the HIV-1 core poly(A) site in vitro. We furthermore show that efficient in vitro 3' processing requires the RNA stem-loop structure of TAR, which serves to juxtapose spatially the upstream element and the core poly(A) site. An analysis of the stability of 3' processing complexes formed at the HIV-1 poly(A) site in vitro suggests that the upstream element may function by increasing processing complex stability at the core poly(A) site.
Human immunodeficiency virus type 1 (HIV-1) RNA contains an extended hairpin structure at the 5' end (the TAR element) that is essential for viral replication. The upper part of the stem-loop structure binds the virally encoded transcriptional activator protein Tat and cellular co-factors, but no clear function for the lower stem region has been established. Here, we report that mutant HIV-1 viruses with base substitutions in the lower stem region are dead, most likely at the level of transcription from an integrated provirus. By using large amounts of these mutant DNA constructs for transfections, revertant viruses with a great variety of genetic changes (point mutations, short deletions) could be isolated in prolonged culture experiments that lasted over 6 months. The pattern and evolution of these changes supported the notion that base-pairing of the lower stem region is essential for optimal HIV-1 replication. The functional and genetic plasticities of this RNA domain and the HIV-1 long terminal repeat promoter are discussed.
The size-exclusion chromatography (SEC) of acetone-soluble, pyridine-soluble and pyridine-insoluble fractions of a coal tar pitch indicates a bimodal distribution in each fraction. The proportion of high-mass material excluded from the SEC column porosity increases with solvent polarity. The polymer calibration of SEC shows the mass range of the small molecules to be from approximately 100 u to approximately 6000 u, with the mass range of the large excluded molecules above 200 000 u and up to several million u. In contrast, matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS) shows a similar low-mass range of ion abundances (< m/z 6000), but with a smaller range of high-mass ion abundances, from approximately m/z 10 000 to 100 000. The large molecules may have three-dimensional structures to allow molecules of relatively low mass to behave as if they are of large size in SEC. Laser desorption mass spectrometry of the acetone- and pyridine-soluble fractions produced molecular ions of polycyclic aromatics that can be related to the known compositions from gas chromatography (GC) mass spectrometry. The experimental conditions used to generate the bimodal distribution by MALDI-MS involve reducing the ion signal intensities to avoid overload of the detector and enable detection of the high-mass ions, by reducing the high-mass detector voltage (i.e. sensitivity) and increasing the laser power.
Hydroquinone (HQ), catechol, and phenol exist in microgram quantities in cigarette tar and represent the predominant form of human exposure to benzene. Exposure of human T lymphoblasts (HTL) in vitro to 50 microM HQ or 50 microM catechol decreased IL-2-dependent DNA synthesis and cell proliferation by >90% with no effect on cell viability. Phenol had no effect on HTL proliferation at concentrations up to 1 mm. The addition of HQ or catechol to proliferating HTL blocked 3H-TdR uptake by >90% within 2 hr without significantly affecting 3H-UR uptake, suggesting that both compounds inhibit a rate-limiting step in DNA synthesis. However, the effects of HQ and catechol appear to involve different mechanisms. Ferric chloride (FeCl3) reversed the inhibitory effect of catechol, but not HQ, corresponding with the known ability of catechol to chelate iron. HQ, but not catechol, caused a decrease in transferrin receptor (TfR, CD71) expression, comparable to the level observed in IL-2-starved cells. HQ also inhibited DNA synthesis in cultures of transformed Jurkat T lymphocytes, primary and transformed fibroblasts, and mink lung epithelial cells, indicating that its antiproliferative effect was not restricted to IL-2 mediated proliferation. However, DNA synthesis by primary lymphocytes was more sensitive to HQ (IC50 = 6 microM) than that of the transformed Jurkat T cell line (IC50 = 37 microM) or primary human fibroblasts (IC50 = 45 microM), suggesting that normal lymphocytes may be particularly sensitive to HQ. The effects of HQ and catechol on DNA synthesis could be partially reversed by a combination of adenosine deoxyribose and guanosine deoxyribose, suggesting that both compounds may inhibit ribonucleotide reductase.
We have used nuclear magnetic resonance (NMR) to obtain the structure of an RNA "kissing" hairpin complex formed between the HIV-2 TAR hairpin loop and a hairpin with a complementary loop sequence. Kissing hairpins are important in natural antisense reactions; their complex is a specific target for protein binding. The complex has all six nucleotides of each loop paired to form a bent quasicontinuous helix of three coaxially stacked helices: two stems plus a loop-loop interaction helix. Experimental constraints derived from heteronuclear and homonuclear NMR data on 13C and 15N-labeled RNA led to a structure for the loop-loop helix with an average root-mean-square deviation of 0.83 (+/-0.10) A for 33 converged structures relative to the average structure. The loop-loop helix of the kissing complex is distorted compared to A-form RNA. Its major groove is blocked by the phosphodiester bonds that connect the first loop residue of each hairpin with its own stem, and it is flanked by two negatively charged phosphate clusters. The loop-loop helix has alternating helical twists between adjacent base-pairs. The base-pairs at the helix junctions are overwound and three base-pairs near the helix junctions adopt high propeller twists. All these changes reduce the distance needed for the bridging phosphodiester bonds connecting each stem and loop to cross the major groove of the loop-loop helix, and result in a deformed RNA helix with localized perturbations in the minor groove surface. The alternating helical twist pattern, plus other distortions in the loop-loop helix may be important for Rom protein recognition of the kissing hairpin complex.
Biological monitoring is an efficient tool in the evaluation of exposure to chemical agents. However, the dose-response of adverse health effects using biological exposure indices and biological limit values are rarely available. This paper presents an estimation of the occupational exposure limit value of 1-hydroxypyrene in urine, a biological exposure indicator of polycyclic aromatic hydrocarbons (PAH). A large-scale study of the exposure of cokeoven workers to PAH, in which both air sampling (benzene soluble matter and individual PAH including benzo(a)pyrene) and biological monitoring (1-hydroxypyrene in urine) were applied, made it possible to establish an empirical mathematical relationship between the air sampling data and biological monitoring data. It was calculated that cokeoven workers with a urinary concentration of 1-hydroxypyrene of 2.3 mumol/mol creatinine after a 3-day working period equals the airborne threshold limit value (TLV) of coal tar pitch volatiles (CTPV). Epidemiological studies have quantified the relative risk of lung cancer for topside and non-topside cokeoven workers. The published environmental exposure data of topside and non-topside cokeoven workers were used to determine the time-average exposure. The data of 1-hydroxypyrene in the urine of cokeoven workers and data of epidemiological studies from different coke plants were combined according to the concentrations of PAH in the air. Thus, it was possible to establish an indirect relationship between lung cancer mortality risk and the biological exposure indicator for cokeoven workers. Exposure at the level of the suggested tentative biological exposure limit (BEL) of 2.3 mumol/mol creatinine is estimated to be equal to a relative risk of lung cancer of approximately 1.3.
TAR RNA-binding protein TRBP was originally isolated by its binding affinity for radiolabeled HIV-1 leader RNA. Subsequent studies have suggested that this protein is one member of a family of double-stranded RNA-binding proteins. Recent findings indicate that TRBP might function to antagonize the translational inhibitory effect that can be mediated through cellular protein kinase, PKR. Here, we report on the over-expression of a cDNA coding for TRBP in eukaryotic SF9 cells using baculovirus. We characterized the nuclear localization of TRBP in insect cells, and we demonstrate that TRBP co-immunoprecipitates with a protein in these cells antigenically related to human PKR. Copyright 1995 S. Karger AG, Basel
TAR syndrome is a rare inherited autosomal recessive disorder with a mortality rate of 30-40% mainly as a result of haemorrhage, in the first year of life. Most of the infants recover from the effects of thrombocytopenia and associated haematological complications with the modern medical care. Very rarely, the outcome is fatal, with the occurrence of acute leukemias.