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Biomedical subjects

R Y Dodd

Publications and source records attributed to R Y Dodd.

At least 55 records · Page 3Linked to original sources
PubMed1994

Viral inactivation in platelet concentrates.

Although the current risk of posttransfusion infection is very low in North America and Western Europe, there continues to be considerable interest in measures to inactivate residual viruses in blood components. The human immunodeficiency virus is of greatest concern, but hepatitis C virus is also considered to be a significant problem. HTLV-I and -II and HBV may also be transmitted by transfusion, although infrequently. It is likely that effective inactivation methods will have to reduce viral titers by about 6 orders of magnitude, including both viruses found free in plasma and those in intracellular compartments. Although it would be most desirable to have a single procedure to inactivate viruses in all blood components, it appears that different methods may be required for plasma, red cells and platelets. To date, the most promising approach for platelets appears to be photochemical inactivation. In general, photoactive compounds fall into two major groups: photodynamic dyes which are activated by visible light and act by oxygen dependent generation of reactive molecular species; and ultraviolet-activated intercalating compounds which form covalent adducts with nucleic acids. We have found that photodynamic inactivators are unable to inactivate viruses in platelet concentrates without damaging the platelets. On the other hand, we have shown that aminomethyl trimethyl psoralen (AMT), when activated by long-wavelength ultraviolet light (UVA) can inactivate more than 5 logs of model viruses and HIV while platelet in vitro properties are maintained. Further, unlike photodynamic inactivators, AMT is able to inactivate cell-associated and intracellular viruses and also prevents the replication of integrated HIV genome sequences, as demonstrated by PCR.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Platelets↗
PubMed1994

The effectiveness of the confidential unit exclusion option.

BACKGROUND: The confidential unit exclusion (CUE) option is intended to reduce human immunodeficiency virus (HIV) transmission by excluding donors newly infected with HIV who have not yet developed HIV antibody (window-period donors); however, its efficacy in excluding window-period donors has not been evaluated. STUDY DESIGN AND METHODS: The use of the CUE option was studied among the donors of 3.7 million units at 18 American Red Cross blood services regions during 1991 and 1992 and among 322 previously HIV-1-seronegative donors who subsequently donated a seropositive unit between 1987 and 1990 at 40 United States blood centers. These seroconverting donors had previously been shown to be highly likely to donate during their window period. RESULTS: On the basis of data from these two populations, it was estimated that only 3 to 5 percent of units donated by window-period donors were not transfused because of the CUE option, that 0.4 percent of all donations were from donors who confidentially excluded their blood from transfusion, and that donors who confidentially excluded their blood were 21 times more likely to be HIV antibody-positive than donors who did not use the CUE option. It is estimated that, if all US blood centers used the CUE option, a total of 2 to 17 otherwise acceptable units donated by window-period donors would not be transfused annually. CONCLUSION: Although donors who confidentially exclude their blood from transfusion are 21 times more likely to have HIV antibody, the rarity of window-period donors and the infrequency of confidential exclusion by window-period donors cause the CUE option to have minimal impact on transfusion safety.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Inactivation of free and cell-associated human immunodeficiency virus in platelet suspensions by aminomethyltrimethylpsoralen and ultraviolet light.

BACKGROUND: It has previously been reported that 40 micrograms per mL of aminomethyltrimethylpsoralen (AMT) plus 2.4 to 7.2 J per cm2 of ultraviolet A (UVA) light inactivated 4 to 6 log10 of several model viruses in platelet suspensions. This inactivation was achieved while satisfactory levels of platelet count, pH, morphology, aggregation, and hemostatic effectiveness were maintained. STUDY DESIGN AND METHODS: The efficacy of this procedure for inactivating free and intracellular human immunodeficiency virus (HIV), including integrated proviral sequences, was studied. RESULTS: The kinetics of inactivation for free HIV (4-5 log10 kill with 1.2-4.8 J/cm2) were similar to those obtained for the previously studied viruses. For studies on cell-associated virus, H9 cells productively infected with HIV were added to platelet suspensions and treated with the above regimen of AMT and UVA. The phototreated cells were then cocultivated with uninfected H9 cells for 4 weeks and supernatants were assayed by enzyme-linked immunosorbent assay for HIV p24. No evidence of HIV replication was detectable for cells receiving as little as 2.4 J per cm2 of UVA irradiation in the presence of AMT. Further, it has been demonstrated that stably integrated sequences from the HIV proviral env gene can no longer be amplified by polymerase chain reaction after 1.2 J per cm2 of UVA (with 40 micrograms/mL AMT) exposure. CONCLUSION: These data suggest that AMT and UVA is an effective antiviral treatment for free and cell-associated HIV in platelet suspensions.

Base Sequence↗
PubMed1994

Transfusion-associated bacterial sepsis.

The incidence of sepsis caused by transfusion of bacterially contaminated blood components is similar to or less than that of transfusion-transmitted hepatitis C virus infection, yet significantly exceeds those currently estimated for transfusion-associated human immunodeficiency and hepatitis B viruses. Outcomes are serious and may be fatal. In addition, transfusion of sterile allogenic blood can have generalized immunosuppressive effects on recipients, resulting in increased susceptibility to postoperative infection. This review examines the frequency of occurrence of transfusion-associated sepsis, the organisms implicated, and potential sources of bacteria. Approaches to minimize the frequency of sepsis are discussed, including the benefits and disadvantages of altering the storage conditions for blood. In addition, the impact of high levels of bacteria on the gross characteristics of erythrocyte and platelet concentrates is described. The potentials and limitations of current tests for detecting bacteria in blood are also discussed.

Bacterial Infections↗
PubMed1993

Assessment of the hemostatic effectiveness of human platelets treated with aminomethyltrimethyl psoralen and UV A light using a rabbit ear bleeding time technique.

The photochemical aminomethyltrimethyl psoralen (AMT), in conjunction with UV A light (UVA), has been shown to inactivate human immunodeficiency virus-1 and model viruses in platelet suspensions under conditions that have only a minimal effect on in vitro platelet properties. A rabbit ear bleeding time technique was used to assess the hemostatic effectiveness of human platelet suspensions treated with AMT/UVA. New Zealand White rabbits were made thrombocytopenic by a combination of irradiation and heterologous antirabbit platelet antiserum. Reticuloendothelial function in these rabbits was suppressed by the intravenous administration of ethyl palmitate. The hemostatic function of 1- and 5-day-old human platelet suspensions (14.5% plasma) that had been treated on day 1 with 40 micrograms/mL AMT and 24 kJ/m2 UVA (1 x UVA) was evaluated by measuring microvascular bleeding times after a standard incision. Comparable bleeding times were observed after infusion with both control and AMT/UVA-treated platelets stored for either 1 or 5 days. With the transfusion of AMT/1 x UVA-treated platelets stored for 5 days, the mean (+/- SD) bleeding time was 156.3 +/- 39.2 seconds (n = 10). With untreated platelets (no AMT/no UVA), stored for 5 days, the mean bleeding time was 189.2 +/- 36.4 seconds (n = 10). Neither AMT nor 1 x UVA treatment alone influenced the observed bleeding times. In contrast, the hemostatic effectiveness of human platelet suspensions was diminished if they were exposed to three times the standard UVA dose (72 kJ/m2) on day 1 and stored for 4 more days, regardless of whether AMT was present, with the mean bleeding time increasing to 442.2 +/- 122.6 seconds (n = 15, AMT present) or 396.0 +/- 45.9 seconds (n = 10, AMT absent). These results are consistent with data obtained from in vitro studies and indicate that virucidal AMT/1 x UVA treatment does not influence platelet hemostatic function. However, the final conditions to achieve these results must be carefully controlled.

Animals↗
PubMed1993

Determination of residual 4'-aminomethyl-4,5',8-trimethylpsoralen and mutagenicity testing following psoralen plus UVA treatment of platelet suspensions.

Psoralens and UVA light have been used in the laboratory to study the inactivation of viruses that may be infrequently present in platelet concentrates that are prepared for transfusion. In order to evaluate safety aspects of the treatment of platelet suspensions with 4'-aminomethyl-4,5',8-trimethylpsoralen (AMT), we have investigated the residual levels and mutagenic potential of AMT after UVA phototreatment. 4'-aminomethyl-4,5',8-trimethylpsoralen, at a final concentration of 40 micrograms/mL, was added to platelet suspensions which contained 16% plasma and a synthetic medium. Platelet suspensions containing AMT were irradiated with up to 7.2 J/cm2 UVA light under normal oxygen levels. Residual levels of AMT were determined by HPLC and a bioassay based on bacteriophage phi 6 inactivation. The photodestruction of AMT or its activity by UVA was characterized by a D37 value of 0.6 and 0.3 J/cm2 with HPLC or bioassay, respectively. At 2.4 J/cm2 UVA, which results in approximately 5 log10 inactivation of vesicular stomatitis virus (VSV) and retention of platelet in vitro properties, 12% (HPLC) to 9% (bioassay) AMT remained. Like other psoralens, AMT was found to bind to serum proteins as shown by ultrafiltration. Results are consistent with approximately 36% of the initial drug load binding primarily to serum albumin. It was determined using 3H-AMT that 9 to 18% of radioactivity was bound to platelets in the absence of irradiation. Similar fractions (13 to 18%) of AMT were bound to platelets after 3.6 J/cm2 UVA irradiation, and 8 to 10% of total AMT was associated with saline-washed irradiated platelets and is presumably tightly bound.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacteriophages↗
PubMed1993

Hepatitis C, other types of non-B parenteral hepatitis and blood transfusion.

Since the implementation of sensitive screening tests for hepatitis B virus infection, the majority of post-transfusion hepatitis has been due to infection with hepatitis C virus (HCV). The recent introduction of tests for antibodies to this virus has demonstrably reduced the incidence of post-transfusion HCV infection. There is some residual post-transfusion and sporadic hepatitis, which may possibly be caused by an as yet undescribed aetiologic agent. However, evidence for or against such an agent is by no means definitive. The majority of cases of this residual hepatitis seem to be mild and progression to chronicity is less frequent than for HCV infection. There is no evidence to suggest that modern, fully inactivated pooled plasma products transmit this poorly characterized form of hepatitis. However, in some circumstances, the potential for transmission of non-enveloped viruses by clotting factors may persist.

Biological Products↗
PubMed1992

Inactivation of microbial contaminants of blood components.

Despite the low risk of transfusion-transmitted infection currently present in the blood supply, processes to inactivate contaminating viruses and bacteria may improve the safety of transfusion even further. A variety of techniques, using both physical and chemical processes, are being explored. Particularly promising is adaptation of the solvent/detergent technique (already in use for plasma derivatives) to plasma for transfusion. Inactivation of viruses in cellular components may require a combination of techniques, possibly including leukocyte depletion filtration, photoactive compounds, and subsequent washing. Concerns about potential toxicity of the agents employed and retention of component efficacy after treatment and storage remain unresolved, however.

Bacteria↗
PubMed1992

Factors influencing virus inactivation and retention of platelet properties following treatment with aminomethyltrimethylpsoralen and ultraviolet A light.

A wide variety of viruses are inactivated by psoralen compounds in the presence of ultraviolet A light (UVA). Use of aminomethyltrimethylpsoralen (AMT) and UVA is being evaluated as a method to inactivate viruses that may be present in platelet suspensions prepared for transfusion. Studies have been conducted to assess how variation in various environmental parameters influences the extent of viral inactivation and the retention of platelet properties. Most notably, it was determined that increasing levels of plasma progressively inhibited the inactivation of model viruses. As a result, experiments were routinely conducted at a plasma level of approximately 14.5%, using 40 micrograms/ml AMT, which was determined to be optimal when using this reduced plasma level. The reduced plasma level was achieved by dilution with a nonplasma medium that has been shown to be satisfactory for storage of platelets. Under these conditions, about 5 logs of vesicular stomatitis virus (VSV), pseudorabies, and phi 6 inactivation were achieved. Variation of platelet and leukocyte counts, within normal levels, had a minimal effect on extent of viral inactivation. Although oxygen level (mean levels, 97.9 mm Hg versus 19.2 mm Hg) had only a small influence on viral inactivation with 2.4, 4.8, and 7.2 J/cm2 of UVA (equivalent to 1-3 minutes of exposure), in vitro platelet properties, such as medium pH, morphology characteristics, and aggregation response, were better retained with a longer exposure time at the reduced oxygen level. With normal oxygen (97.9 mm Hg), platelet properties declined substantially relative to untreated controls (no UVA, no AMT) on exposure to 4.8 J/cm2. Our studies have identified two sets of conditions that provide about 5 logs of virus inactivation without extensively altering platelet in vitro properties.

Blood↗
PubMed1991

Human immunodeficiency virus infection and indeterminate western blot patterns. Prospective studies in a low prevalence population.

Interpretation of human immunodeficiency virus (HIV) antibody results that are "indeterminate" rather than clearly positive or negative is problematic for the person delivering the result as well as for the individual being tested. To improve counseling messages for these individuals, we evaluated data collected from a well-characterized cohort of 387 blood donors who had been monitored for up to 2 years. We sought to determine if persons with indeterminate Western blot patterns were infected with HIV, and whether information derived from follow-up monitoring would assist in the development of counseling messages for persons on whom no follow-up information was available. Donors were studied by laboratory assays, clinical evaluation, and assessment of risk for HIV. The absence of HIV infection in 97 of 98 donors with indeterminate Western blot patterns was confirmed by clinical follow-up, Western blot assays of sequential samples, and negative gene amplification results. We propose supplemental guidelines to be used as an adjunct to existing interpretive criteria for counseling individuals when they first present with an indeterminate Western blot finding.

Acquired Immunodeficiency Syndrome↗
PubMed1990

The western immunoblot procedure for HIV antibodies and its interpretation.

The Western blot is frequently used to confirm human immunodeficiency virus type 1 (HIV-1) screening tests as it permits the identification of antibodies to individual component polypeptides of HIV-1. The procedure is described and different criteria for evaluation of HIV-1 Western blots are compared. The significance and management of indeterminate blot patterns are discussed.

Blotting, Western↗
PubMed1989

Exposure of patients to human immunodeficiency virus through the transfusion of blood components that test antibody-negative.

The risk of transmission of the human immunodeficiency virus to recipients of blood transfusions exists chiefly during the period between the time a donor is infected and the time he or she has a positive blood test for HIV antibodies. Estimating the chance that blood will be donated during this period is an effective way to define the risk of HIV infection from transfusion. Using this approach, and employing data from over 17 million American Red Cross blood donations, we estimate that during 1987 the most likely number of units of blood infected with undetected HIV that were transfused was 131 (range, 67 to 227). For a patient, the odds of contracting HIV infection were 1:153,000 per unit transfused. A patient who received the average transfusion (5.4 units) had odds of 1:28,000. The risk has been decreasing by more than 30 percent a year. We estimate that donor-recruitment practices plus careful education and screening are eliminating 49 of every 50 donors likely to be HIV-positive and that testing is 92 to 97 percent effective, for a combined effectiveness of 99.9 percent. The risk of undetected infectious units can probably be further reduced by transfusing fewer units and units from fewer donors, recruiting more women and fewer men as new donors, and encouraging more frequent donations from donors who have been tested repeatedly.

AIDS Serodiagnosis↗