Low- vs high-dose aspirin. Effects on platelet function in hyperlipoproteinemic and normal subjects.

Low-dose aspirin may be inadequate for inhibition of platelet function in hyperlipoproteinemics due to increased platelet reactivity. Platelet function was studied in 18 type II hyperlipoproteinemic and 12 normal subjects after at least ten days of treatment with placebo and with low-dose (0.45 mg/kg/day) and high-dose (900 mg/day) aspirin. In the normal and hyperlipoproteinemic subjects, low-dose aspirin produced near maximal (90%) inhibition of platelet thromboxane generation, significant prolongation of the bleeding time, and significant inhibition of platelet aggregation, similar in degree to the inhibition produced by high-dose aspirin. There was no significant difference between hyperlipoproteinemic and normal subjects in any of the platelet function measures before and after aspirin treatment. Thus, a daily 0.45-mg/kg aspirin dose (20 to 45 mg) effectively inhibited platelet function in type II hyperlipoproteinemics, who do not appear to have an increased dose requirement for aspirin.

Omega-3 fatty acids in hypertriglyceridemic patients: triglycerides vs methyl esters.

The purpose of this study was to compare the relative effects of omega-3 fatty acids (omega-3 FAs) in the triglyceride (TG) and methly ester (ME) forms in a crossover design in patients with type IV hyperlipidemia. Eight male patients were given 18 vegetable-oil capsules (control); 18 capsules of a TG rich in omega-3 FAs (omega-3 TG); and 11 capsules containing omega-3-FA MEs (omega-3 ME). One supplement was given during each of three 6-wk periods. Equivalent amounts of omega-3 FAs (6.8 g/d) were provided by each of the omega-3 treatments. Plasma cholesterol (C) levels were unchanged during the two omega-3 phases whereas plasma TG levels fell by 44% during both. Low-density-lipoprotein cholesterol (LDL-C) levels rose significantly with both omega-3-FA treatments, as did apolipoprotein B levels. When taken in either the TG or ME forms, omega-3 FAs are equally effective hypotriglyceridemic agents but they may raise LDL-C levels.

Synergy, activity and tolerability of zidovudine and interferon-alpha in patients with symptomatic HIV-1 infection: AIDS Clincal Trial Group 068.

Thirty-four subjects with symptomatic HIV-1 infection, p24 antigenaemia, and CD4 cell counts > 200/mm3 were randomly assigned to receive treatment with either zidovudine (ZDV) orally, interferon-alpha (IFN-alpha) subcutaneously, or both at respective low (200 mg ZDV/ 2 million international units IFN-alpha (MIU)), middle (400 mg/4 MIU) or high (600 mg/6 MIU) daily dose levels for 12 weeks. Thereafter, all patients received combination therapy at the initially assigned dose level to a total of 96 weeks. This design permitted analysis by the combination index (CI) method, which demonstrated antiretroviral synergy between ZDV and IFN-alpha with respect to p24 antigen suppression. Over the first 12 weeks, combination therapy was acceptably tolerated, more so than IFN-alpha monotherapy, and it was significantly more active in suppressing antigenaemia than either of the monotherapies. Similarly, the high-dose combination was the most active dose level over weeks 12 to 96. Combination ZDV/IFN-alpha at the optimal dose level defined by this trial merits further study. In addition, the CI design strategy employed here may be useful for the investigation of new antiretroviral combinations.

Effects of dietary fish oil on platelet function and plasma lipids in hyperlipoproteinemic and normal subjects.

We studied the effects of dietary supplementation with an encapsulated fish oil concentrate (Maxepa) on platelet function, fibrinolysis, and plasma lipids and lipoproteins in 9 normal subjects, 10 patients with type IV hyperlipoproteinemia, and 6 with type IIB hyperlipoproteinemia. After a baseline period, the subjects crossed over randomly between treatment periods with Maxepa (providing 3.24 g eicosapentaenoic acid and 2.16 g docosahexaenoic acid per day) and safflower oil (used as a control), given for 6 weeks each. Administration of Maxepa led to a slight prolongation of the bleeding time in all groups and to modest inhibition of platelet aggregation in the type IV hyperlipoproteinemics and normal subjects, with partial (41%) inhibition of thromboxane synthesis from baseline levels noted in the normal group. Plasma total fibrinolytic actively did not change significantly in any group. Maxepa treatment resulted in a marked decrease in triglyceride and VLDL-cholesterol and a slight increase in HDL-cholesterol was noted after Maxepa in the type IV hyperlipoproteinemics (4.11 +/- 0.13 mmol/l vs. 3.10 +/- 0.16 mmol/l, Maxepa vs. safflower oil). We conclude that dietary supplementation with fish oil results in a relatively minor degree of inhibition of platelet function in normal and hyperlipoproteinemic subjects, and a potentially adverse increase in LDL-cholesterol in type IV hyperlipoproteinemics.

The effect of 5'-amino-5'-deoxythymidine on the pattern of polyadenylation of herpes simplex virus type 1 ribonucleic acid.

Treatment of herpes simplex virus type 1 (HSV-1) infected Vero cells with 5'-amino-5'-deoxythymidine (AdThd) causes a 65% reduction in the amount of total viral RNA present at late times of infection. This decrease is apparent as early as 6 hours post infection, affecting the levels of viral cytoplasmic polyadenylated (poly(A+] species to a greater extent than non-polyadenylated (poly(A-] RNA. Cytoplasmic viral poly(A+) RNA is present in AdThd-treated cultures at only 10% control poly(A+) levels, yet there is no evidence of a direct inhibition of RNA polyadenylation. Underrepresentation of RNA species in the cytoplasm is not sequence-specific. The results suggest that the antiviral activity of AdThd may involve not only incorporation into viral DNA, with a resultant decrease in viral transcription, but also perturbation of the relative amounts of viral poly(A+) RNA and poly(A-) RNA.

Effect of diltiazem and low-dose aspirin on platelet aggregation and ATP release induced by paired agonists.

The authors studied the effects of diltiazem, administered alone and together with low-dose aspirin, on the platelet response to paired agonists. After a baseline period, 25 healthy volunteers were given oral diltiazem for 1 week (120, 240, or 360 mg/day), and then crossed over randomly between 1 week on diltiazem plus aspirin (81 mg/day), and 1 week on aspirin (81 mg/day) alone. Platelet function was tested on 2 consecutive days in each period. Synergistic platelet aggregation and ATP release were obtained at baseline using a subthreshold concentration of arachidonic acid combined with platelet activating factor, ADP, or epinephrine. Diltiazem resulted in significant decrease from baseline in platelet aggregation and ATP release using the arachidonic acid-epinephrine combination (35% and 40% decrease, respectively, p < 0.01) and a significant decrease in aggregation using the arachidonic acid-ADP combination (22% decrease, p < 0.01). The effects were neither dose-related, nor accompanied by any significant change in serum thromboxane B2 levels or bleeding times. There was no significant difference between the effects of aspirin alone and aspirin plus diltiazem on the synergistic platelet aggregation and ATP release induced by the paired agonists, or on thromboxane B2 levels or bleeding times. Diltiazem administered in vivo partially inhibits the synergistic platelet aggregation and ATP release induced by paired agonists; however, in contrast to a previous in vitro study it does not potentiate the platelet-inhibitory effect of aspirin.

Effect of incorporation of 5-iodo-2'-deoxyuridine into HSV-1 DNA on virion sensitivity to ultraviolet light.

First generation progeny herpes simplex type 1 (HSV-1) virions grown in the presence of 5-iodo-2'-deoxyuridine (IdUrd) were irradiated with either 254 or 302 nm ultraviolet (u.v.) light. The kinetics of virus inactivation revealed decreased sensitivity of IdUrd-substituted virions to irradiation with 302 nm light under all conditions examined, and with 254 nm u.v. light when substituted and control virions were irradiated at equal particle concentrations. Comparison of virus survival after irradiation measured in Vero or Xeroderma Pigmentosum (complementation group A) cells indicated that cellular repair of ultraviolet-induced lesions was not a significant factor in the observed decrease in u.v. sensitivity. IdUrd substitution altered neither the formation of ultraviolet-induced thymidine photoproducts nor the ability of irradiated virions to express delayed early viral enzymes (thymidine kinase, DNA polymerase). It is suggested that nucleocapsid proteins or the highly ordered structure of IdUrd-substituted virions play a key role in u.v. desensitization, either by the formation of non-lethal photoproducts or by the prevention of the formation of DNA-uracilyl free radicals.

Production of herpes simplex virus type 1 thymidine kinase in the presence of thymidine analogues.

Treatment of herpes simplex virus type 1 (HSV-1) infected Vero, BHK, BHKtk- and LMtk- cells with 5-iodo-5'-amino-2',5'-dideoxyuridine (AIdUrd) caused increased synthesis of ICP36 and an increase in HSV-1 thymidine kinase (tk) activity at late times of infection. The overproduced ICP36 was identified as the HSV-1 encoded tk protein by immunoprecipitation. Whereas the thymidine analogue 5'-amino-5'-deoxythymidine (AdThd) caused an increase in HSV-1 tk synthesis and activity in wild type Vero and BHK cells, 5-iodo-2'-deoxyuridine (IdUrd) caused a similar increase only in tk- cells (LMtk-, BHKtk-). In vivo and in vitro stabilization studies using a [35S]methionine pulse-chase experiment or heat inactivation studies with purified HSV-1 tk revealed that stabilization of tk by the analogues could not account for the extent of the observed increase. Since overproduction of tk is observed only at late times of infection, it is suggested that the presence of these thymidine analogues in either the viral DNA or the cellular nucleotide pools is responsible for the observed differential effects.

The effect of combined antenatal vitamin K and phenobarbital therapy on umbilical blood coagulation studies in infants less than 34 weeks' gestation.

OBJECTIVE: To determine if antenatal vitamin K and phenobarbital therapy affect coagulation studies in umbilical blood at birth, and to provide 95% reference ranges for umbilical blood coagulation parameters in premature gestations. METHODS: Patients at imminent risk for spontaneous or indicated premature delivery less than 34 weeks' gestation were randomized to receive either placebo or vitamin K and phenobarbital. Prothrombin time (PT), activated partial thromboplastin time (PTT), functional coagulation factors, and decarboxylated prothrombin assays were performed on umbilical blood specimens. Decarboxylated prothrombin, also known as "protein induced by vitamin K absence-factor II" or precursor prothrombin, is a sensitive marker for vitamin K deficiency. Standardized values of PT and PTT are reported in seconds and standardized values of factor assays in percentage of normal adult functional activity (mean +/- one standard deviation). RESULTS: Newborns in the placebo and treatment groups had similar umbilical blood PT (12.6 +/- 1.2 versus 12.7 +/- 1.4 seconds), PTT (48.8 +/- 13.4 versus 49.6 +/- 13.8 seconds), and functional activity of factor II (40.3 +/- 12.5 versus 42.0 +/- 12.1%), factor VII (67.0 +/- 20.9 versus 66.8 +/- 18.9%), factor IX (27.4 +/- 12.8 versus 25.8 +/- 8.9%), and factor X (47.0 +/- 12.8 versus 49.2 +/- 11.6%). Newborns in the treatment group were about half as likely as those in the placebo group to have detectable decarboxylated prothrombin levels in umbilical blood at birth (gestational age-adjusted odds ratio 0.47, 95% confidence interval 0.22-1.01; P = .05). CONCLUSIONS: Combined maternal therapy with vitamin K and phenobarbital before premature delivery does not affect umbilical blood PT, PTT, or functional activity of vitamin K-dependent coagulation factors II, VII, IX, and X. However, it is associated with the reduced presence of decarboxylated prothrombin in umbilical blood at birth. There is significant improvement in umbilical blood coagulation tests as gestational age advances from 24 to 34 weeks.

The use of blood and blood components in 1,769 patients undergoing open-heart surgery.

There has been a decrease in the use of whole blood and red cell transfusions during and after open-heart operations in the greater Kansas City area from an average of slightly more than 9 units per patient from 1969 through 1971, to just over 3 units per patient from 1975 through 1977. In 1977, 1,256 patients, or 71% of 1,769 patients, underwent coronary artery bypass exclusively and had an average transfusion utilization of 2.6 units. All other open-heart operations averaged 4.7 units per patient. Hemodilution and the acceptance of hematocrits between 25 and 30% in open-heart operations are probably the main factors responsible for lower transfusion use per patient, while the increased proportion of patients undergoing coronary artery bypass accounts for a further decrease in the average amount of blood used per patient. It is of note that blood transfused to patients having an open-heart operation was not significantly fresher than blood for routine use, yet hemostasis was not a problem as evidenced by the small use of fresh-frozen plasma in 67 patients (3.8%) and platelet concentrates in 42 patients (2.4%).

The effect of variable fat diets and cholesterol-lowering drugs on Antithrombin III levels in hyperlipoproteinemic and normal subjects.

Functional and immunological Antithrombin III (AT III) levels were studied in normal and hyperlipoproteinemic subjects undergoing crossover therapeutic trials of either diets or hypocholesterolemic drugs. The diet trial subjects, 7 hyperlipoproteinemics and 15 normals, were randomly assigned to crossover between a high saturated fat diet (P/S ratio 1:8) and a high polyunsaturated fat diet (P/S ratio 4:1) for periods of 6-8 weeks, preceded by a baseline period on regular American diet (P/S ratio 1:1). For the drug trials, 33 type II A or B hyperlipoproteinemics were treated in random and double-blind fashion with Colestipol (20 gm/day) or both, for periods of 3 months, preceded by a double placebo period. Mean low density lipoprotein cholesterol levels were significantly different (p less than 0.001) between high saturated and high polyunsaturated fat diets (157 +/- 37 mg/dl vs 137 +/- 31 mg/dl respectively, mean +/- S.D.) and between placebo and drug treatment periods (226 +/- 51 mg/dl vs 183 +/- 44 mg/dl respectively, mean + S.D.). There was no difference in basal functional or immunological AT III levels between normal and hyperlipoproteinemics. AT III levels did not correlate significantly with cholesterol or triglyceride levels and remained unchanged despite significant reductions in serum cholesterol related to the diet and drug therapy. There appears to be no significant association between baseline or post treatment serum cholesterol levels and functional or immunological AT III. Thus, changes in AT III are unlikely to play a role in the link between hypercholesterolemia and thrombosis.

Treating eating-disorder patients in a managed care environment. Contemporary American issues and Canadian response.

This article addresses the effect of managed care on the treatment of eating disorders. We review strategies for negotiating limitations that managed care reviewers place on treatment. Finally, this article reviews the experiences of a Canadian program that has 10 years of experience in providing low-cost day treatment. While change is frustrating and difficult, it is inevitable and can be rejuvenating. These changes offer opportunities for creative development of quality low-cost care. If we do not adjust to these conditions, patients will not get treatment that they need.

Activated clotting time (ACT) testing: analysis of reproducibility.

Activated Clotting Time (ACT) has been the standard for monitoring heparin anticoagulation in cardiac surgery for three decades. Although a 10% coefficient of variation (CV) is the referenced standard for the test, no recent reports of precision are available. The precision of Hemochron FTCA510 (celite) and KACT (kaolin) ACT test tubes was evaluated using a retrospective analysis of results from both laboratory studies and routine clinical usage. Laboratory studies of reproducibility included analysis of the CV from repetitive testing using multiple lots of ACTs. Substrates used included 40 consecutive lots of control plasma and freshly heparinized donor blood. Across the lots of control plasma, the celite ACT yielded an average CV of 5.4% for the normal control level and 4.0% in the abnormal control level (range 3.6-9.7% and 2.7-6.3%, respectively). The KACT showed similar performance for the normal (mean = 4.5%, range 2.2-7.8%) and abnormal (mean = 3.8%, range 2.0-10.0%). These values, significantly less than 10%, reflect the combined variability of both the ACT tests and the lyophilized, single use vial, control material. Fresh whole blood samples exhibited improved ACT precision when compared to this artificial substrate. CVs for the celite ACT range from 0.6-6.0% at one unit heparin/ml blood to 2.4-11.6% at 5 units/ml where clotting times exceed 650 sec. The KACT showed even lower CVs at all heparin levels, with values of 2.4-7.0%. Clinical evaluations included samples (N = 56) collected from cardiac surgery patients with celite ACT values ranging to 744 sec. Duplicate values differed by an average of 7.5 sec or 1.8%. There was only one clinically significant difference in paired values; a 376 sec paired with a 406 sec, 400 sec being the clinical target time. This retrospective data analysis demonstrates that Hemochron ACT variability is significantly less than 10%.

An adult case of acute biphenotypic leukemia with characteristic mixed morphology.

A case of acute biphenotypic leukemia with mixed blast morphology and combined myeloid and T-lymphoid features is reported. The leukemic cells consisted of small lymphoid hand-mirror blasts and large blasts with cytoplasmic granules and rare Auer rods. The cells expressed myeloid and immature T-lymphoid features by cytochemistry and immunophenotyping, however T cell receptor genes were in germline configuration. Cases of biphenotypic leukemia with similar morphological and immunophenotypic findings have been described previously in children. This case represents a morphologically and phenotypically distinct subtype of acute biphenotypic leukemia.

Mechanism of thrombocytopenia in chronic hepatitis C as evaluated by the immature platelet fraction.

INTRODUCTION: Thrombocytopenia occurs frequently in chronic hepatitis C. The mechanism of this association was investigated utilizing the immature platelet fraction (IPF%) as an index of platelet production together with assay of thrombopoietin (TPO). METHODS: In a cross-sectional study, 47 patients with chronic hepatitis C were studied, 29 with thrombocytopenia and 18 without thrombocytopenia (six patients in each group were on interferon therapy). RESULTS: IPF% was elevated in the thrombocytopenic compared with the nonthrombocytopenic group (9.0 ± 4.8% vs. 4.7 ± 2.4%, P < 0.001), and an increase in IPF% was significantly associated with thrombocytopenia on multivariable analysis (P < 0.05). Splenomegaly was more common in thrombocytopenic than in nonthrombocytopenic subjects (66% vs. 6%, P < 0.001), and on multivariable analysis, splenomegaly was the factor associated with the highest relative risk of thrombocytopenia (RR = 1.9, P < 0.05). IPF% values were elevated in a similar proportion of thrombocytopenic patients with and without splenomegaly (58% and 60%, respectively). There was no difference in TPO levels between thrombocytopenic and nonthrombocytopenic patients, and TPO levels were not related to the risk of thrombocytopenia on multivariable analysis. Significantly more thrombocytopenic than nonthrombocytopenic subjects had abnormal liver function tests, cirrhosis, and portal hypertension, and a decrease in serum albumin was significantly associated with thrombocytopenia (P < 0.005) on multivariable analysis. CONCLUSIONS: Factors associated with liver disease in general are associated with thrombocytopenia in chronic hepatitis C. Peripheral platelet destruction or sequestration is the major mechanism for thrombocytopenia, with hypersplenism being an important cause. Low TPO levels were not related to the occurrence of thrombocytopenia in this study.

Recombinant DNA related to hepatitis B and human immunodeficiency viruses in mononuclear cells of patients with AIDS.

Sixty-eight of 73 patients with human immunodeficiency virus (HIV) infection were positive when tested for the presence of hepatitis B virus (HBV)-related DNA sequences in peripheral blood mononuclear cells (PBMCs) by the dot blot method. Twenty-two of the positive DNAs were examined by Southern hybridization and all exhibited a 3.2 kb extrachromosomal DNA fragment that hybridized to HBV DNA. This DNA was isolated from agarose gels and cloned into the EcoRI site of pBR322 DNA. The cloned DNA (pHBI) hybridized to both HBV DNA and HIV cDNA; HBV DNA did not hybridize to HIV cDNA under the same conditions. The results of restriction enzyme analyses indicated that pHBI contains: 1) a large deletion of HBV sequences spanning the 3' end of the HBV surface antigen gene; 2) a small deletion near the 5' end of the HBV core antigen gene; and 3) a region of homology to a one kb central section of the HIV pol gene. These data suggest that the 3.2 kb DNA found in the PBMCs is a natural recombinant between HBV and HIV DNAs raising the possibility not only that this DNA plays a role in the pathogenesis of AIDS but also that other viral recombinant DNAs may be pathogenic in human disease.

Infection and transformation of mouse cells by human adenovirus type 2.

The susceptibilities of C57Bl/6J mouse embryo fibroblasts (MEF) and baby mouse kidney (BMK) cells to infection or transformation by adenovirus type 2 have been compared to those of rat embryo fibroblasts (REF). Both MEF and BMK cells were some 10-fold less permissive to replication of the virus than were REF cells, even though similar fractions of all three cell types, a maximum of 50-60%, produced viral tumor and structural antigens. This observation suggests that a very late step in adenovirus production, such as assembly or maturation, occurs much less efficiently in mouse cells than it does in rat cells. No significant differences in the frequencies of transformation, as assayed by the appearance of foci of morphologically transformed cells, were observed following transfection of adenovirus type 2 or type 5 DNA into the three cell types. However, it proved extremely difficult to establish permanent lines of adenovirus-transformed mouse cells: only 2 of more than 100 attempts were successful, compared to a success rate of close to 100% with adenovirus type 2-transformed REF or SV40-transformed MEF or BMK cells. The two lines of type 2 adenovirus-transformed MEF that were established have been shown to retain and express viral genetic information.

Inhibition of human immunodeficiency virus type 1 replication by nonionic block polymer surfactants.

Eight block copolymers of hydrophilic polyoxyethylene and hydrophobic polyoxypropylene were examined for their effects on the replication of human immunodeficiency virus type 1 (HIV-1) in H9 cells. Although the polymers decreased cellular replication, they did not appear to be toxic to the cells; rather, they seemed to arrest cellular growth. Three triblock copolymers were found to inhibit HIV replication at low concentrations. Maximum inhibition was achieved at concentrations of 50 micrograms/ml by day 5 following infection. The combination of azidothymidine with both HIV-1-inhibitory and noninhibitory copolymers resulted in antagonistic effects, with an increase in viral replication, compared to treatment with copolymers or azidothymidine alone. These copolymers should be useful in the study of the mechanism of HIV replication in cell cultures and may yield clinically useful compounds in combination therapies for HIV infection.