Myocardial infarction complicating gastrointestinal hemorrhage

OBJECTIVE: To determine the frequency of and risk factors for myocardial infarction (MI) in patients admitted to an intensive-care unit (ICU) with gastrointestinal (GI) hemorrhage and to ascertain the effects on mortality and lengths of stay. MATERIAL AND METHODS: Demographic, laboratory, and outcome data were determined for all patients admitted to a medical ICU with GI hemorrhage between April 1996 and January 1997. Serial creatine kinase with isoenzyme levels and electrocardiograms were interpreted blindly by a senior cardiologist. RESULTS: For 83 consecutive admissions to the ICU because of GI hemorrhage, the patients' mean (+/- standard error) age was 65.0 +/- 1.7 years and APACHE II (acute physiology and chronic health evaluation) score was 15.7 +/- 0.8. In-hospital death occurred in 16 patients (19%). Patients who did not survive had a lower admission systolic blood pressure (99.2 +/- 4.5 versus 115.0 +/- 4.0 mm Hg; P = 0.01) than did those who survived. Eleven of 83 patients (13%) fulfilled both enzymatic and electrocardiographic criteria for MI. Ten patients (12%) had electrocardiographic evidence of myocardial ischemia but did not meet criteria for MI. Patients with MI were older (74.4 +/- 4.0 versus 61.7 +/- 2.0 years; P < 0.05), had a higher acuity of illness (APACHE II score, 21.6 +/- 3.0 versus 14.6 +/- 0.7; P < 0.05), and had more coronary risk factors (2.3 +/- 0.3 versus 1.4 +/- 0.1; P < 0.05) in comparison with those without MI or ischemia. Patients with MI also had longer ICU (8.6 +/- 2.4 versus 3.3 +/- 0.4 days; P < 0.05) and hospital (16.3 +/- 3.4 versus 9.1 +/- 0.8 days; P < 0.05) lengths of stay. Patients older than 65 years had a threefold increased risk (risk ratio, 4.0; 95% confidence interval, 0.9 to 17.4) and those with two or more risk factors for coronary artery disease had a ninefold increased risk of MI (risk ratio, 10.2; 95% confidence interval, 1.4 to 76.1) in comparison with those who were younger or who had fewer coronary risk factors, respectively. MI complicating GI hemorrhage did not significantly affect the risk of in-hospital mortality (risk ratio, 1.5; 95% confidence interval, 0.5 to 4.4). CONCLUSION: MI occurs frequently in patients with GI hemorrhage admitted to an ICU. Age more than 65 years and two or more risk factors for coronary artery disease identify patients who are at greatest risk for occurrence of MI, which is associated with longer ICU and hospital stays.     

The oral bioavailability of pentosan polysulphate sodium in healthy volunteers

Objective: Pentosan polysulphate sodium (PPS), a heparin-like drug, is supposed to be orally applicable. The objective of the present study was to assess the oral bioavailability of PPS. However, since specific assays for PPS do not exist, this was done by using primary and secondary effect parameters. Methods: The study was carried out using a three-way randomized crossover design with 18 healthy young male volunteers. The subjects received three treatments: PPS i.v. (50 mg), PPS orally (1500 mg) and placebo (orally). Blood sampling was done for activated partial thromboplastin time (APTT), anti-Xa activity, hepatic triglyceride lipase, lipoprotein lipase, tissue plasminogen activator (t-PA) activity, fibrin plate lysis, total triglyceride, total cholesterol, HDL and LDL. Results: Intravenously administered PPS significantly increased APTT, anti-Xa activity, hepatic triglyceride lipase and lipoprotein lipase compared with placebo in a magnitude comparable to other i.v. heparin-like compounds. Orally administered PPS did not significantly influence any of the parameters when compared with placebo. Point estimates for the oral bioavailability of PPS were in the range of 0% with small confidence intervals (CIs). Conclusion: The oral bioavailability of PPS is negligible in young healthy males. Received: 8 June 1998 / Accepted in revised form: 19 October 1998     

Inhibition of deoxynucleotide-polymerizing enzyme activities of human leukemia lymphoblasts and simian sarcoma virus by tilorone and thirteen of its analogs.

Tilorone, which is 2,7-bis[2-(diethylamino)ethoxy]-9H-fluoren-9-one dihydrochloride, and 13 of its analogs inhibited human cellular DNA polymerases alpha and beta assayed with activated DNA as template and also cellular DNA polymerase gamma and DNA polymerase from simian sarcoma virus assayed with poly(A) (dT)12-18 as template. Terminal deoxynucleotidyltransferase (TdT), which has no template requirement, was not inhibited by any of the 14 compounds when d(A)12-18 or d(G)12-18 was used as initiator. Three compounds did not inhibit TdT assayed with activated DNA as initiator, but 11 compounds did, and these 11 compounds were generally less inhibitory to TdT than to the other DNA polymerases. The three compounds that did not inhibit TdT assayed with activated DNA but did inhibit the other DNA polymerases will be useful in the characterization of TdT activity. Modifications of the polycyclic ring structure of tilorone and the kinds of substituent groups attached to the ring structures influenced the degree of inhibition of all enzymes.     

Sensitivity and tolerance to nicotine in smokers and nonsmokers

We studied the responses of smokers and life-long non-smokers to transdermal nicotine patches over 24 h in three groups of subjects: non-smokers on a 15 mg patch (n=8), non-smokers on a 30 mg patch (n=8) and smokers on a 30 mg patch (n=8). Unexpectedly, the non-smokers appeared to absorb nicotine more rapidly. The increase in blood nicotine concentrations of non-smokers over the first 2 h of patch use was double that of the smokers, with mean increases of 4.5 (SD=3.7), 10.9 (SD=4.2) and 4.1 (SD=2.7) ng/ml in the three groups, respectively (P<0.005). The smokers had no pleasant or unpleasant effects from the 30 mg patch ( C_max 13.9 ng/ml, SD=4.9; T_max 8.75 h) but all eight non-smokers experienced mild nausea and lightheadedness (P<0.01) within the first hour, and seven dropped out (P<0.01) at 3–8 h due mainly to severe nausea, vomiting or headache ( C_max 18.4 ng/ml, SD=4.9; T_max 5.25 h). Only one non-smoker dropped out on the 15 mg patch, but five had transient nausea in the first hour ( C_max 7.9 ng/ml, SD=3.0; T_max 8.0). Our study provides evidence of chronic pharmacodynamic nicotine tolerance in smokers, but does not address whether this is acquired or innate. The higher rate of transdermal nicotine absorption in non-smokers is unexplained and requires replication.     

In vitro binding of gibberellin A(4) to extracts of cucumber measured by using DEAE-cellulose filters

A rapid method for assaying [³H]gibberellin A₄ bound to a soluble protein from cucumber hypocotyls by using DEAE-cellulose filter discs is described. The binding is saturable, reversible with unlabeled gibberellin A₄, and has a half-life of association under nonequilibrium conditions at 0-4°C of 6-7 min. By using this assay, the dissociation constant (K_d) was estimated to be 70 nM and the number of binding sites, 0.4 pmol mg^-1 of soluble protein or 0.69 pmol g^-1 (fresh weight) of hypocotyls. The speed and reliability of the assay make it invaluable for kinetic studies involving competitors. Thus, it has been possible to show that gibberellins that are biologically active in a cucumber bioassay compete for binding to the same protein and their calculated affinity constants bear a direct relationship to their known activities in the cucumber bioassay. Gibberellins that are inactive in this bioassay and other plant hormones, such as indoleacetic acid, abscisic acid, and kinetin, show a noncompetitive interaction.     

Deoxynucleotide-polymerizing enzyme activities in T- and B-cells of acute lymphoblastic leukemia origin.

All 5 thymus-dependent cell (T-cell) lines (Molt-3; Molt-4; RPMI-8402; CCRF-CEM; CCRF-HSB-2) and 7 thymus-independent cell (B-cell) lines (RPMI-8382, RPMI-8392, RPMI-8412, RPMI-8422, RPMI-8432, RPMI-8442, CCRF-SB) established so far from acute lymphoblastic leukemia patients were examined for deoxynucleotide polymerizing enzymes. All T- and B-cells had DNA polymerase gamma, DNA polymerase beta, and terminal deoxynucleotidyl transferase both in the soluble (the latter 2 enzymes only in small amounts) and chromatin fraction, whereas DNA polymerase alpha was found only in the soluble fraction. With respect to their sedimentation and chromatographic behavior, template-primer requirements, Km for deoxythymidine triphosphate or deoxyguanosine triphosphate divalent cation preference, effect of NaCI and inhibitors, the enzymes from T- and B-cells resembled each other and those from other mammalian cells. DNA polymerase alpha, beta, and gamma from T-cells like those from "fresh" acute lymphoblastic leukemia cells, were more thermolabile than those from B-cells or phytohemagglutinin-stimulated normal lymphocytes. In addition, the terminal deoxynucleotidyl transferase from the above cells was completely inactivated in 5 to 6 min at 50 degrees, whereas the DNA polymerase alpha, beta, and gamma retained considerable activity even after heating for 25 min at 50 degrees. DNA polymerase activity of the soluble fraction from T-cells was of the same magnitude as in B-cells when expressed on a DNA basis but twice that of B-cells when expressed on a protein basis. High terminal deoxynucleotidyl transferase activity, equivalent to that observed in acute lymphoblastic leukemia cells, was found in all T-cell lines that, when expressed on a DNA basis, was 30 to 100 times higher than the B-cell lines tested. These results support the suggestion of earlier investigators that T-cell lines examined here may have originated from leukemic cells.     

Aneuploidy of chromosome 9 and the tumor suppressor genes p16(INK4) and p15(INK4B) detected by in situ hybridization in locally advanced prostate cancer

INTRODUCTION AND OBJECTIVES: The linked p16(INK4)/MTS1 and p15(INK4B)/MTS2 genes on chromosome 9p21 encode proteins that inhibit the cyclinD dependent kinases CDK4/6. Biallelic homozygous deletions involving this locus have been identified in a wide range of tumor cell lines, but in a lower frequency of primary tumors. As PCR based approaches analyzing for homozygous deletions could be confounded by unavoidable contributions of normal cells in microdissected tissue, we performed in situ hybridization (ISH) on primary prostate carcinomas to accurately evaluate p16 and p15 copy numbers on a cell-by-cell basis. MATERIAL AND METHODS: p16 and p15 loci were evaluated in 28 pT3N0M0 prostate cancer specimens. Of 28 patients, 15 (53%) were ascertained showing no recurrence (mean follow-up 61+/-17 months), 13 (47%) developed recurrences within 27+/-19 months. Tissues were provided for ISH analysis in a blinded fashion. Isolated DNA derived from P1 clone 1063 compromising p16 and p15 as well as a centromeric probe for chromosome 9 were used for hybridization. Signals were enumerated within 300 interphase nuclei per tumor specimen, and in 100 nuclei derived from 18 benign prostate tissues and 7 adjacent PIN regions. RESULTS: ISH detected aneuploid tumors in 12/13 (92%) patients with recurrence and in 5/15 (33%) without recurrence (p<0.0014). Whereas 3/7 PIN specimens associated with nonrecurrent PCA demonstrated euploidy, all 4/7 PIN associated with recurrent disease demonstrated the same aneuploidy for chr9 as the primary tumor. All benign tissues evaluated exhibited euploidy for chr9, p16 and p15. None of the PCA and PIN samples revealed homozygous deletions for p16(INK4)/MTS1/p15(INK4B)/MTS2; 2/28 (7.1%) PCA exhibited partial deletion for p16(INK4)/MTS1/p15(INK4B)/MTS2 and aneuploidy for chr9; both PCA derived from the recurrent group. CONCLUSIONS: Deletion of 9p21 was rare and therefore such genetic alterations may not play an important role in the pathogenesis of PCA. Analysis of the limited number of PCA examined suggest a strong association between chr9 aneuploidy and recurrenct disease. Aneuploidy in both PIN and PCA suggests that the clinical outcome of PCA might already be determined in the preinvasive PIN.