ISIS Penning source extraction studies reveal the 3-dimensional Child-Langmuir effect.

The standard 1X ISIS negative Penning surface plasma source has reliably produced an H- beam for ISIS operations for 35 years. In order to meet the 60 mA, 2 ms, and 50 Hz beam current and duty cycle required for the front end test stand (Letchford et al., in Proceedings of IPAC2015, Richmond, VA, USA, 2015), a 2X scaled source has been developed [Faircloth et al., AIP Conf. Proc. 2052, 050004 (2018)]. The 2X source has a plasma chamber twice the linear dimensions of the 1X source. This paper investigates the comparison between different emission areas (plasma electrode aperture dimensions) for both the 1X and 2X sources. Slit and circular extraction schemes are studied. A 3D Child-Langmuir relationship is observed where the space charge limited current density depends on the aspect ratio of the extraction aperture.

Recent H- diagnostics, plasma simulations, and 2X scaled Penning ion source developments at the Rutherford Appleton Laboratory.

A vessel for extraction and source plasma analyses is being used for Penning H- ion source development at the Rutherford Appleton Laboratory. A new set of optical elements including an einzel lens has been installed, which transports over 80 mA of H- beam successfully. Simultaneously, a 2X scaled Penning source has been developed to reduce cathode power density. The 2X source is now delivering a 65 mA H- ion beam at 10% duty factor, meeting its design criteria. The long-term viability of the einzel lens and 2X source is now being evaluated, so new diagnostic devices have been installed. A pair of electrostatic deflector plates is used to correct beam misalignment and perform fast chopping, with a voltage rise time of 24 ns. A suite of four quartz crystal microbalances has shown that the cesium flux in the vacuum vessel is only increased by a factor of two, despite the absence of a dedicated cold trap. Finally, an infrared camera has demonstrated good agreement with thermal simulations but has indicated unexpected heating due to beam loss on the downstream electrode. These types of diagnostics are suitable for monitoring all operational ion sources. In addition to experimental campaigns and new diagnostic tools, the high-performance VSim and COMSOL software packages are being used for plasma simulations of two novel ion thrusters for space propulsion applications. In parallel, a VSim framework has been established to include arbitrary temperature and cesium fields to allow the modeling of surface physics in H- ion sources.

A comparative assessment of the acute inhalation toxicity of vanadium compounds.

Vanadium compounds have become important in industrial processes, resulting in workplace exposure potential and are present in ambient air as a result of fossil fuel combustion. A series of acute nose-only inhalation toxicity studies was conducted in both rats and mice in order to obtain comparative data on the acute toxicity potential of compounds used commercially. V2O3, V2O4, and V2O5, which have different oxidation states (+3, +4, +5, respectively), were delivered as micronized powders; the highly water-soluble and hygroscopic VOSO4 (+4) could not be micronized and was instead delivered as a liquid aerosol from an aqueous solution. V2O5 was the most acutely toxic micronized powder in both species. Despite its lower overall percentage vanadium content, a liquid aerosol of VOSO4 was more toxic than the V2O5 particles in mice, but not in rats. These data suggest that an interaction of characteristics, i.e., bioavailability, solubility and oxidation state, as well as species sensitivity, likely affect the toxicity potential of vanadium compounds. Based on clinical observations and gross necropsy findings, the lung appeared to be the target organ for all compounds. The level of hazard posed will depend on the specific chemical form of the vanadium. Future work to define the inhalation toxicity potential of vanadium compounds of various oxidation states after repeated exposures will be important in understanding how the physico-chemical and biological characteristics of specific vanadium compounds interact to affect toxicity potential and the potential risks posed to human health.

Relationship of plasma N-terminal pro-brain natriuretic peptide concentrations to heart failure classification and cause of respiratory distress in dogs using a 2nd generation ELISA assay.

BACKGROUND: Cardiac biomarkers provide objective data that augments clinical assessment of heart disease (HD). HYPOTHESIS/OBJECTIVES: Determine the utility of plasma N-terminal pro-brain natriuretic peptide concentration [NT-proBNP] measured by a 2nd generation canine ELISA assay to discriminate cardiac from noncardiac respiratory distress and evaluate HD severity. ANIMALS: Client-owned dogs (n = 291). METHODS: Multicenter, cross-sectional, prospective investigation. Medical history, physical examination, echocardiography, and thoracic radiography classified 113 asymptomatic dogs (group 1, n = 39 without HD; group 2, n = 74 with HD), and 178 with respiratory distress (group 3, n = 104 respiratory disease, either with or without concurrent HD; group 4, n = 74 with congestive heart failure [CHF]). HD severity was graded using International Small Animal Cardiac Health Council (ISACHC) and ACVIM Consensus (ACVIM-HD) schemes without knowledge of [NT-proBNP] results. Receiver-operating characteristic curve analysis assessed the capacity of [NT-proBNP] to discriminate between dogs with cardiac and noncardiac respiratory distress. Multivariate general linear models containing key clinical variables tested associations between [NT-proBNP] and HD severity. RESULTS: Plasma [NT-proBNP] (median; IQR) was higher in CHF dogs (5,110; 2,769-8,466 pmol/L) compared to those with noncardiac respiratory distress (1,287; 672-2,704 pmol/L; P < .0001). A cut-off >2,447 pmol/L discriminated CHF from noncardiac respiratory distress (81.1% sensitivity; 73.1% specificity; area under curve, 0.84). A multivariate model comprising left atrial to aortic ratio, heart rate, left ventricular diameter, end-systole, and ACVIM-HD scheme most accurately associated average plasma [NT-proBNP] with HD severity. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma [NT-proBNP] was useful for discriminating CHF from noncardiac respiratory distress. Average plasma [NT-BNP] increased significantly as a function of HD severity using the ACVIM-HD classification scheme.

Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment.

Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose-response data (Gollapudi et al., 2013), here we present analyses of 1-ethyl-1-nitrosourea (ENU) and 1-methyl-1-nitrosourea (MNU) dose-response data and additional approaches for the determination of genetic toxicity point-of-departure (PoD) metrics. We previously described methods to determine the no-observed-genotoxic-effect-level (NOGEL), the breakpoint-dose (BPD; previously named Td), and the benchmark dose (BMD10 ) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non-linear slope-transition-dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL10 and BMDL1SD PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due to data limitations and constraints of the underlying statistical methods. The BMDL10 values were often lower than the other PoDs, and the distribution of BMDL10 values produced the lowest median PoD. Our observations indicate that, among the methods investigated in this study, the BMD approach is the preferred PoD for quantitatively describing genetic toxicology data. Once genetic toxicology PoDs are calculated via this approach, they can be used to derive reference doses and margin of exposure values that may be useful for evaluating human risk and regulatory decision making.

Investigation into the characteristics, triggers and mechanism of apnoea and bradycardia in the anaesthetized platypus (Ornithorhynchus anatinus).

Health and conservation research on platypuses (Ornithorhynchus anatinus) may require anaesthesia to reduce stress and the risk of injury to both the animal and the researcher, as well as to facilitate examination and sample collection. Platypus anaesthesia can be difficult to manage, with reports of periods of apnoea and bradycardia described. This study investigated the conditions around sudden-onset apnoea and bradycardia in 163 field-anaesthetized platypuses as part of a health study. Anaesthesia was induced and maintained using isoflurane delivered in oxygen by face mask. Sudden-onset apnoea and bradycardia was observed in 19% of platypuses, occurring either at induction of anaesthesia, during recovery, or both. At induction, occurrence was more often recorded for adults (P = 0.19) and was correlated with low body temperature (P < 0.001), season (P = 0.06; greater incidence in summer) and longer pre-anaesthetic holding time (P = 0.16). At recovery, sudden-onset apnoea and bradycardia occurred only in platypuses that had been placed in dorsal recumbency as part of their examination, and correlated with poor body condition (P = 0.002), time in dorsal recumbency (P = 0.005), adults (P = 0.06), number of fieldworkers (P = 0.06) and females (P = 0.11). The sudden-onset apnoea and bradycardia we observed is likely to result from the irritant nature of isoflurane (stimulating the trigeminal nerve via nasal chemoreceptors). We propose that this mechanism is analogous to that of submersion of the face/nasal cavity in cold water during a natural dive response, but that the term 'nasopharyngeal response' would more appropriately describe the changes observed under isoflurane anaesthesia. Although we did not record any long-term adverse effects on platypuses that had undergone this response, the nasopharyngeal response could complicate the diagnosis of anaesthetic dose-dependent apnoea and bradycardia. Therefore, we suggest that these responses during anaesthesia of platypuses might be avoided by minimizing the stress around capture and handling, as well as reducing the time in dorsal recumbency.

Quantitative approaches for assessing dose-response relationships in genetic toxicology studies.

Genetic toxicology studies are required for the safety assessment of chemicals. Data from these studies have historically been interpreted in a qualitative, dichotomous "yes" or "no" manner without analysis of dose-response relationships. This article is based upon the work of an international multi-sector group that examined how quantitative dose-response relationships for in vitro and in vivo genetic toxicology data might be used to improve human risk assessment. The group examined three quantitative approaches for analyzing dose-response curves and deriving point-of-departure (POD) metrics (i.e., the no-observed-genotoxic-effect-level (NOGEL), the threshold effect level (Td), and the benchmark dose (BMD)), using data for the induction of micronuclei and gene mutations by methyl methanesulfonate or ethyl methanesulfonate in vitro and in vivo. These results suggest that the POD descriptors obtained using the different approaches are within the same order of magnitude, with more variability observed for the in vivo assays. The different approaches were found to be complementary as each has advantages and limitations. The results further indicate that the lower confidence limit of a benchmark response rate of 10% (BMDL(10) ) could be considered a satisfactory POD when analyzing genotoxicity data using the BMD approach. The models described permit the identification of POD values that could be combined with mode of action analysis to determine whether exposure(s) below a particular level constitutes a significant human risk. Subsequent analyses will expand the number of substances and endpoints investigated, and continue to evaluate the utility of quantitative approaches for analysis of genetic toxicity dose-response data.

Identification of lobar fissures in pathological lungs.

Identification of lobar fissures in human lungs is a non-trivial task due to their variable shape and appearance, along with the low contrast and high noise in computed tomographic (CT) images. Pathologies in the lungs can further complicate this identification by deforming and/or disrupting the lobar fissures. Current algorithms rely on the general anatomy of the lungs to find fissures affected by pathologies. This can be unreliable as deformations and/or disruptions of these fissures will alter the general lung anatomy. To overcome this, we developed an algorithm with the following novelties: (1) a new application of neural network based texture analysis to generalize fissure regions; and (2) a new method of fissure surface identification. We tested our algorithm on CT image stacks from 8 anonymous patients with pathological lungs. Compared to manually segmented fissures, our algorithm produced an average mean difference of 0.71 mm and 0.68 mm for identifying the left and right oblique fissures, respectively. Using a 3-mm percentile measure, the algorithm yielded an average accuracy of 86.8% for the left oblique fissure with a mean worst-case error of 3.18 mm. For the right oblique fissure, the algorithm produced an accuracy of 88.8% with a mean worst-case error of 3.13 mm. The above results show feasibility of using our algorithm for identifying fissures in pathological lungs.

Preliminary investigation into the prevalence of mucormycosis in the platypus (Ornithorhynchus anatinus) in three catchments in north-west Tasmania.

OBJECTIVE: To investigate the distribution and prevalence of mucormycosis in platypus (Ornithorhynchus anatinus) from the Inglis, Emu and Black-Detention catchment areas in north-west Tasmania. PROCEDURE: A field study was performed and resulted in the examination of 44 wild platypuses; in addition, one dead platypus and two live platypuses were examined after they were independently submitted to a local veterinary clinic. RESULTS: No cases of mucormycosis were conclusively diagnosed. One platypus with signs consistent with those previously described in cases of mucormycosis was captured in the Emu River catchment. However, laboratory tests did not provide a definitive diagnosis for the lesion. Two platypuses from the Inglis catchment area had signs very similar to those previously described in cases of mucormycosis, but laboratory tests found Corynebacterium ulcerans to be the likely cause of the cutaneous ulcers on one of these platypuses and an unidentified fungal agent to be the cause of a cutaneous nodule in the other. CONCLUSIONS: These findings do not prove that mucormycosis is absent from the populations studied. However, they may indicate that the prevalence of disease is low. The possibility that Mucor amphibiorum is present in a subclinical form in platypuses, or infecting another reservoir, is not excluded. The findings also suggest that caution should be exercised when diagnosing mucormycosis based on clinical findings alone and raise the possibility that some cases may have been incorrectly diagnosed.

Regulatory aspects of genotoxicity testing: from hazard identification to risk assessment.

This symposium focused on the use of tests for chromosomal damage, and other genotoxicity measures, for detection of potentially harmful chemicals. The speakers discussed the information that has been gained over the last three decades about the use of "short-term tests" for genotoxicity in cultured cells and in animals (mainly rodents), and the ongoing debates about the rational use of data from such experimental systems in trying to extrapolate to an understanding of potential human risk. The overall theme was that the field of regulatory toxicology currently is over-reliant on qualitative outcomes of in vitro hazard-screening tests, generally conducted at the maximum achievable exposures, and needs a more realistic approach that incorporates in vivo exposure levels and dose-response information.

Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression.

In this report, we developed a chimeric receptor (N29gamma chR) involving the single chain Fv (scFv) derived from N29 monoclonal antibody (mAb) specific for p185HER2 and characterized the therapeutic efficacy of primary T cells engineered to express N29gamma chR in two histologically distinct murine tumor models. Murine breast (MT901) and fibrosarcoma (MCA207) cancer cell lines were engineered to express human HER2 as targets. Administration of N29gamma chR-expressing T cells eliminated 3-day pulmonary micrometastases of MT901/HER2 and MCA207/HER2 but not parental tumor cells. A 5 to 8-fold increased dose of N29gamma T cells was required to mediate regression of advanced 8-day macrometastases. Exogenous administration of interleukin-2 (IL-2) after N29gamma T-cell transfer was dispensable for treatment of 3-day micrometastases, but was required for mediating regression of well-established 8-day macrometastases. Moreover, fractionated CD8 T cells expressing N29gamma chR suppressed HER2-positive tumor cell growth after adoptive transfer independent of CD4(+) cells. These data indicate that genetically modified T cells expressing a HER2-targeting chimeric receptor can mediate antigen-specific regression of preestablished metastatic cancers in a cell dose-dependent fashion. Systemic administration of IL-2 augments the therapeutic efficacy of these genetically engineered T cells in advanced diseases. These results are relevant to the implication of genetically redirected T cells in clinical cancer immunotherapy.

Segmentation of lung lobes in isotropic CT images using wavelet transformation.

Advanced multi-slice CT scanners produce isotropic CT images, which have pixel dimensions equal to their image thicknesses of 0.6 mm. Comparing to clinical standard CT images with a thickness of 2.5 - 7.0 mm, isotropic CT images have clearly visible lobar fissures. This poses a challenge for developing automatic algorithms to identify the fissure locations and curvatures. This paper presents a wavelet algorithm that allows automatic identification of the left and right oblique fissures, as well semi-automatic identification of the horizontal fissures. This algorithm took a two-stage approach: (a) adaptive fissure sweeping to find fissure regions; and (b) wavelet transform to identify the fissure locations and curvatures within these fissure regions. Tested on 8, 6 and 6 stacks of isotropic CT images for the left oblique, right oblique and horizontal fissures, respectively, the algorithm yielded an accuracy of 77.1 - 93.6% with strict evaluation criteria. This provides promising potential for developing an automatic algorithm to segment lung lobes.

Strategy for genotoxicity testing: hazard identification and risk assessment in relation to in vitro testing.

This report summarizes the proceedings of the September 9-10, 2005 meeting of the Expert Working Group on Hazard Identification and Risk Assessment in Relation to In Vitro Testing, part of an initiative on genetic toxicology. The objective of the Working Group was to develop recommendations for interpretation of results from tests commonly included in regulatory genetic toxicology test batteries, and to propose an appropriate strategy for follow-up testing when positive in vitro results were obtained in these assays. The Group noted the high frequency of positive in vitro findings in the genotoxicity test batteries with agents found not to be carcinogenic and thought not to pose a carcinogenic health hazard to humans. The Group agreed that a set of consensus principles for appropriate interpretation and follow-up testing when initial in vitro tests are positive was needed. Current differences in emphasis and policy among different regulatory agencies were recognized as a basis of this need. Using a consensus process among a balanced group of recognized international authorities from industry, government, and academia, it was agreed that a strategy based on these principles should include guidance on: (1) interpretation of initial results in the "core" test battery; (2) criteria for determining when follow-up testing is needed; (3) criteria for selecting appropriate follow-up tests; (4) definition of when the evidence is sufficient to define the mode of action and the relevance to human exposure; and (5) definition of approaches to evaluate the degree of health risk under conditions of exposure of the species of concern (generally the human). A framework for addressing these issues was discussed, and a general "decision tree" was developed that included criteria for assessing the need for further testing, selecting appropriate follow-up tests, and determining a sufficient weight of evidence to attribute a level of risk and stop testing. The discussion included case studies based on actual test results that illustrated common situations encountered, and consensus opinions were developed based on group analysis of these cases. The Working Group defined circumstances in which the pattern and magnitude of positive results was such that there was very low or no concern (e.g., non-reproducible or marginal responses), and no further testing would be needed. This included a discussion of the importance of the use of historical control data. The criteria for determining when follow-up testing is needed included factors, such as evidence of reproducibility, level of cytotoxicity at which an increased DNA damage or mutation frequency is observed, relationship of results to the historical control range of values, and total weight of evidence across assays. When the initial battery is negative, further testing might be required based on information from the published literature, structure activity considerations, or the potential for significant human metabolites not generated in the test systems. Additional testing might also be needed retrospectively when increase in tumors or evidence of pre-neoplastic change is seen. When follow-up testing is needed, it should be based on knowledge about the mode of action, based on reports in the literature or learned from the nature of the responses observed in the initial tests. The initial findings, and available information about the biochemical and pharmacological nature of the agent, are generally sufficient to conclude that the responses observed are consistent with certain molecular mechanisms and inconsistent with others. Follow-up tests should be sensitive to the types of genetic damage known to be capable of inducing the response observed initially. It was recognized that genotoxic events might arise from processes other than direct reactivity with DNA, that these mechanisms may have a non-linear, or threshold, dose-response relationship, and that in such cases it may be possible to determine an exposure level below which there is negligible concern about an effect due to human exposures. When a test result is clearly positive, consideration of relevance to human health includes whether other assays for the same endpoint support the results observed, whether the mode or mechanism of action is relevant to the human, and - most importantly - whether the effect observed is likely to occur in vivo at concentrations expected as a result of human exposure. Although general principles were agreed upon, time did not permit the development of recommendations for the selection of specific tests beyond those commonly employed in initial test batteries.

Segmentation of lung lobes in volumetric CT images for surgical planning of treating lung cancer.

Study has shown that three-dimensional (3D) visualization of lung cavities has distinct advantages over traditional computed tomographic (CT) images for surgical planning. A crucial step for achieving 3D visualization of lung cavities is the segmentation of lung lobes by identifying lobar fissures in volumetric CT images. Current segmentation algorithms for lung lobes rely on manually placed markers to identify the fissures. This paper presents an autonomous algorithm that effectively segments the lung lobes without user intervention. This algorithm applies a two-stage approach: (a) adaptive fissure sweeping to coarsely define fissure regions of lobar fissures; and (b) watershed transform to refine the location and curvature of fissures within the fissure regions. We have tested this algorithm on 4 CT data sets. Comparing with visual inspection, the algorithm provides an accuracy of 85.5-95.0% and 88.2-92.3% for lobar fissures in the left and right lungs, respectively. This work proves the feasibility of developing an automatic algorithm for segmenting lung lobes.

Gene expression profiles and genetic damage in benzo(a)pyrene diol epoxide-exposed TK6 cells.

Microarray analysis is a powerful tool to identify the biological effects of drugs or chemicals on cellular gene expression. In this study, we compare the relationships between traditional measures of genetic toxicology and mutagen-induced alterations in gene expression profiles. TK6 cells were incubated with 0.01, 0.1, or 1.0 microM +/-anti-benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide (BPDE) for 4 h and then cultured for an additional 20 h. Aliquots of the exposed cells were removed at 4 and 24 h in order to quantify DNA adduct levels by 32P post-labeling and measure cell viability by cloning efficiency and flow cytometry. Gene expression profiles were developed by extracting total RNA from the control and exposed cells at 4 and 24 h, labeling with Cy3 or Cy5 and hybridizing to a human 350 gene array. Mutant frequencies in the Thymidine Kinase and Hypoxanthine Phosphoribosyl Transferase genes were also determined. The 10alpha-(deoxyguanosin-N(2)-yl)-7alpha,8beta,9beta-trihydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene (dG-N(2)-BPDE) adduct increased as a function of dose and was the only adduct identified. A dose-related decrease in cell viability was evident at 24 h, but not at 4 h. Cell death occurred by apoptosis. At 4 h, analysis of the gene expression profiles revealed that Glutathione Peroxidase and Gadd45 were consistently upregulated (greater than 1.5-fold and significantly (P < 0.001) greater than the control in two experiments) in response to 1.0 microM BPDE exposure. Fifteen genes were consistently down-regulated (less than 0.67-fold and significantly (P < 0.001) lower than the control in two experiments) at 4 h in cultures exposed to 1.0 microM BPDE. Genes with altered expression at 4 h included genes important in the progression of the cell-cycle and those that inhibit apoptosis. At 24 h post-exposure, 16 genes, involved in cell-cycle control, detoxification, and apoptosis were consistently upregulated; 10 genes were repressed in cultures exposed to the high dose of BPDE. Real-time quantitative PCR confirmed the differential expression of selected genes. These data suggest that changes in gene expression will help to identify effects of drugs and chemicals on molecular pathways in cells, and will provide useful information about the molecular responses associated with DNA damage. Of the endpoints evaluated, DNA adduct formation was the most sensitive indicator of DNA damage. DNA adduct formation was clearly evident at low doses, but the number of genes with significantly altered expression (P < 0.001) was minimal. Alterations in gene expression were more robust at doses associated with cellular toxicity and induction of mutations.

Disease in Africa: a medical perspective from the 1950s.

So much attention is focused on the current HIV/AIDS epidemic in Africa that there is a tendency to overlook the grievous burden of disease from which the peoples of that Continent have suffered for centuries. This paper, based on letters sent in 1953/54 by a young doctor in Sierra Leone to his parents in Scotland, together with extracts from Makeni Hospital records of the same period, provides a factual account of front-line medicine in West Africa half a century ago.

Immunohematotoxicity studies with combinations of dapsone and zidovudine.

We investigated the immunohematoxicities of the antiparasitic drug dapsone (DDS) and the antiretroviral drug zidovudine (ZDV, AZT) given alone or in combination in BALB/c mice. DDS is used for prophylaxis and treatment of Pneumocystis carinii infection in AIDS patients. We examined the impact of concurrent administration of these drugs on the immune and hematopoietic systems because DDS causes hematotoxicity and ZDV therapy results in bone marrow toxicity. Daily oral administration of DDS at 25 and 50 mg/kg for 28 days caused a slight anemia, marked methemoglobinemia, reticulocytosis, and a moderate leukopenia (P < 0.01 for all parameters) but had no discernible effect on platelet count. In DDS-treated mice, the proliferative response of splenic T cells to concanavalin A was > or = 35% higher than that manifested by splenocytes from vehicle-treated control mice. ZDV at 240 and 480 mg/kg was not immunosuppressive but caused low-grade macrocytic anemia, thrombocytosis, and neutropenia; these effects were drug dose-dependent and statistically significant (P < 0.01). Concurrent administration of DDS and ZDV augmented the severity of ZDV-mediated macrocytic anemia, and 7 of 12 (58%) mice did not survive treatment with the high doses of DDS and ZDV (50 and 480 mg/kg, respectively). On the other hand, co-administration of ZDV mitigated DDS-induced methemoglobinemia and the DDS-associated elevation in lymphoproliferative response. These data suggest interaction between DDS and ZDV in mice and indicate a need for caution in using DDS as long-term therapy in AIDS patients receiving ZDV.