Multi-modal responses to the Virtual Reality Trier Social Stress Test: A comparison with standard interpersonal and control conditions.

The Trier Social Stress Test (TSST) is a reliable social-evaluative stressor. To overcome limitations of the in vivo TSST, a standardized virtual reality TSST (VR-TSST) was developed. The present study compares the emotional (anxiety) and physiological (heart period and variability) response to a VR-TSST with an in vivo TSST and a control condition. Participants took part in either an in vivo TSST (N = 106, 64% female), VR-TSST (N = 52, 100% female), or a control TSST (N = 20, 40% female). Mixed linear modeling examined response profile differences related to TSST type. While there was an equivalent anxiety response to the in vivo TSST as the VR-TSST, we found a smaller heart period and heart rate variability response in VR-TSST compared to the in vivo TSST, especially in response to the math part of the test. The present findings demonstrate that social evaluative stress can be successfully induced in a VR setting, producing similar emotional and slightly attenuated cardiovascular responses.

Drug resistance and virologic response in NUCA 3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously untreated patients.

OBJECTIVE: To study the effect of HIV-1 resistance to lamivudine (3TC) and zidovudine (ZDV), and syncytium-inducing (SI) phenotype on virologic response to treatment with ZDV, 3TC, or ZDV plus 3TC in previously untreated individuals with HIV-1 infection. DESIGN: A prospective virologic substudy of GlaxoWellcome protocol NUCA 3001. METHODS: HIV-1 isolates obtained at study entry and at week 12 were expanded in peripheral blood mononuclear cell (PBMC) culture, titered, and assayed for phenotypic and genotypic evidence of resistance to ZDV and 3TC, and for syncytium formation on MT-2 cells. RESULTS: Phenotypic and genotypic resistance to 3TC was detected in the majority of HIV-1 isolates from patients who received 3TC alone or in combination with ZDV. Despite showing 3TC resistance, subjects who received 3TC in combination with ZDV had significantly greater decreases in plasma HIV-1 RNA levels compared with those who received ZDV alone. Occurrence of the K7OR ZDV resistance mutation was significantly reduced in patients who received the 3TC/ZDV combination as compared with patients on ZDV monotherapy. Plasma HIV-1 RNA returned to near-baseline levels more quickly in patients with SI isolates at study entry. CONCLUSIONS: Despite the rapid emergence of 3TC resistance, combination therapy with 3TC plus ZDV resulted in greater reduction in plasma HIV-1 RNA levels over 24 weeks as compared to ZDV monotherapy. Prevention of ZDV resistance may contribute to the sustained activity of the combination therapy.

The sld mutation is specific for sublingual salivary mucous cells and disrupts apomucin gene expression.

NFS/N-sld mice harbor a spontaneous autosomal recessive mutation, sld (sublingual gland differentiation arrest) and histologically display attenuated mucous cell expression in sublingual glands (Hayashi et al. Am J Pathol 132: 187-191, 1988). Because altered serous demilune cell expression is unknown, we determined the phenotypic expression of this cell type in mutants. Moreover, we evaluated whether absence of glycoconjugate staining in 3-day-old mutant glands is related to disruption in apomucin gene expression and/or to posttranslational glycosylation events. Serous cell differentiation is unaffected, determined morphologically and by serous cell marker expression (PSP, parotid secretory protein; and Dcpp, demilune cell and parotid protein). Conversely, apical granules in "atypical" exocrine cells of mutant glands are PSP and mucin negative, but contain abundant SMGD (mucous granule marker). Age-related appearance of mucous cells is associated with expression of apomucin gene products, whereas SMGD expression is unaltered. "Atypical" cells thus appear specified to a mucous cell fate but do not synthesize mucin glycoproteins unless selectively induced postnatally, indicating the sld mutation disrupts apomucin transcriptional regulation and/or decreases apomucin mRNA stability.

The gene encoding mouse Muc19: cDNA, genomic organization and relationship to Smgc.

We previously demonstrated expression of full-length transcripts for sublingual mucin apoprotein, Muc19, of approximately 24 kb (Fallon MA, Latchney LR, Hand AR, Johar A, Denny PA, Georgel PT, Denny PC, and Culp DJ. Physiol Genomics 14: 95-106, 2003). We now describe the complete sequence and genomic organization of the apomucin encoded by 43 exons. Southern analyses indicate a central exon of approximately 18 kb containing 36 tandem repeats, each encoding 163 residues rich in serine and threonine. Full-length transcripts are an estimated 22,795 bp in length that span 106 kb of genomic DNA. The transcriptional start site is 24 bp downstream of a TATA box and 42 bp upstream of the conceptual translational start codon. The putative apoprotein has an estimated mass of 693.4 kDa and contains 7,524 amino acids (80% serine, threonine, glycine, alanine, and proline). We present a model for rat Muc19 transcripts and compare the conceptually translated Muc19 proteins for mouse, rat, pig, and the 3' end of human Muc19. Conserved among these apoproteins are a signal peptide, a large tandem repeat region, von Willebrand factor type C and D domains, a trypsin inhibitor-like Cys-rich domain, and a COOH-terminal cystine knot-like domain. Southern blot analyses indicate transcripts for Muc19 and Smgc (submandibular gland protein C) are splice variants of a larger gene, Muc19/Smgc. Comparative Northern analyses between the major salivary glands demonstrate highly selective Muc19 expression in neonatal and adult sublingual glands, whereas Smgc is expressed in neonatal submandibular and sublingual glands. Regulation of Muc19/Smgc gene expression is discussed with respect to alternative splicing and mucous cell cytodifferentiation.

Effects of gonadal steroid suppression on skeletal sensitivity to parathyroid hormone in men.

Hypogonadism is associated with osteoporosis in men. GnRH- agonist-induced hypogonadism increases bone turnover and bone loss in men, but the mechanism underlying these changes is unknown. To determine whether gonadal steroid deprivation increases the skeletal sensitivity to PTH or blunts the ability of PTH to promote 1,25-dihydroxyvitamin D formation, we infused human PTH-(1-34) at a dose of 0.55 U/kg.h for 24 h, in 11 men (ages, 50-82 yr) with locally advanced, node-positive, or biochemically recurrent prostate cancer but no evidence of bone metastases. PTH infusions were performed before initiation of GnRH agonist therapy (leuprolide acetate, 22.5 mg im, every 3 months) and again after 6 months of confirmed GnRH agonist-induced hypogonadism. Serum osteocalcin (OC), bone- specific alkaline phosphatase (BSAP), N-telopeptide (NTX), whole-blood ionized calcium, and 1,25-dihydroxyvitamin D were measured at baseline and every 6 h during each PTH infusion. Urinary NTX and free deoxypyridinoline (DPD) were assessed on spot morning samples before PTH infusion and on 24-h samples collected during the PTH infusions. Sex steroid levels were lowered to the castrate range in all subjects. Baseline serum NTX levels (drawn before PTH infusion) increased from 9.1 +/- 3.7 before leuprolide therapy to 13.9 +/- 5.0 nmol bone collagen equivalents (BCE)/L after leuprolide therapy (P = 0.003). Spot urine NTX collected before PTH infusion increased from 28 +/- 8 before leuprolide therapy to 49 +/- 17 nmol BCE/mmol creatinine after leuprolide therapy (P < 0.001), and urinary DPD increased from 4.7 +/- 1.1 to 7.4 +/- 1.8 nmol BCE/mmol creatinine (P < 0.001). Baseline serum OC and BSAP levels drawn before each PTH infusion did not change before vs. after leuprolide therapy. Serum NTX levels increased significantly during PTH infusion pre-GnRH agonist therapy (P < 0.001), and the rate of increase was greater after 6 months of GnRH agonist-induced hypogonadism (P < 0.01 for the difference in rates of change before and after GnRH agonist administration). Serum OC and BSAP levels decreased during PTH infusion (P < 0.001 for OC and P = 0.002 for BSAP), but the rates of decrease did not differ before or after leuprolide therapy (P = 0.45 for OC and P: = 0.19 for BSAP). Whole-blood ionized calcium levels increased during PTH infusion (P < 0.001), and the rate of increase was greater after GnRH agonist-induced hypogonadism (P = 0.068). Serum 1,25-dihydroxyvitamin D levels increased in response to PTH infusion before leuprolide therapy (P = 0.022), but there was no difference in the rate of increase before or after leuprolide therapy (P = 0.66). The incremental increase in urinary NTX excretion, but not DPD, during PTH infusion was greater after 6 months of leuprolide therapy (P = 0.029 for NTX, P = 0.578 for DPD). We conclude that suppression of sex steroids in elderly men increases the skeletal responsiveness to the bone resorbing effects of PTH infusion but does not affect the response of bone formation markers or 1,25-dihydroxyvitamin D to PTH. Changes in skeletal sensitivity to PTH may play an important role in the pathogenesis of hypogonadal bone loss in men.

Prevention of chronic rejection and graft arteriosclerosis by tolerance induction.

Chronic rejection is a major cause of graft failure in solid organ transplants after the first year. A characteristic lesion in a variety of chronically rejecting organs is a fibrointimal proliferative arteriosclerosis. It has been speculated that approaches to tolerance induction may be effective in obviating not only acute, but also chronic, rejection. A picture of chronic rejection develops naturally in heart grafts transplanted from the Lewis-to-F-344 strain of rat. We examined whether tolerance induction by bone marrow transplantation and development of hematopoietic chimerism or tolerance induction by intrathymic inoculation of alloantigen could effectively prevent chronic rejection in an established model of chronic rejection. Bone marrow chimeras were developed in F-344 hosts by transplantation of T cell-depleted allogeneic marrow (TCD A BMT). Another set of F-344 hosts was inoculated with intrathymic allogeneic bone marrow cells. Heart grafts in these animals demonstrated tolerance for 120 days after transplantation. Control F-344 animals treated with a short course of cyclosporine consistently developed chronic rejection by 120 days following heart transplantation. Strikingly absent from the tolerant animals was any sign of graft arteriosclerosis, which was demonstrated in the vast majority of control animals. Analysis of cytokine mRNA profiles at 30 days following heart transplantation demonstrated differences between control and tolerant animals. These results suggest that tolerance induction can effectively prevent chronic rejection.

Induction of specific tolerance to small-bowel allografts.

BACKGROUND: The induction of specific tolerance would greatly improve survival and functional state of organ transplant recipients. One approach that has recently received attention is the creation of mixed hematopoietic chimerism through the transplantation of allogeneic and syngeneic T-cell-depleted (TCD) bone marrows. In these studies we examined whether tolerance to highly immunogenic small-bowel transplants could be induced by mixed allogeneic chimerism. Tolerance induction depends on the sharing of antigens between bone marrow cells and small-bowel tissue. METHODS: Adult Lewis rats were lethally irradiated and reconstituted with a mixture of 50 x 10(6) TCD bone marrow cells. Thirty days after reconstitution, animals were tested for chimerism by fluorescence-activated cell sorter analysis. Chimeric animals then received ACI heterotopic small-bowel allografts and were assessed daily for rejection. Small-bowel allograft survival was compared to three control groups: (1) untreated Lewis recipients, (2) irradiated TCD syngeneically reconstituted Lewis recipients, and (3) Lewis bone marrow recipients that did not develop chimerism. RESULTS: Median graft survival in control groups was 8 days. Graft survival in eight mixed chimeras ranged from more than 135 to more than 304 days (p < 0.0001), and no episode of rejection or graft-versus-host disease was observed. Mixed lymphocyte reactivity of chimeric lymphocytes confirmed in vivo observation of tolerance. CONCLUSIONS: Bone marrow cells share tissue-specific antigens with small-bowel cells to permit induction of tolerance.

The role of flow cytometry in the diagnosis of lymphoma: a critical analysis.

Flow cytometry, now used routinely to aid in the classification of leukemias, is increasingly being evaluated as a rapid technique for determination of surface antigens on the cells teased from lymph nodes and other masses with suspected lymphoma. The present study reviews biopsy specimens from patients examined during a two year period which were sent for flow cytometry with a diagnosis of suspected lymphoma. Sixteen of 25 samples (64 percent) produced cell suspensions of sufficient quantity and quality to be diagnostically helpful. Results showed that in 9/16 (56 percent) the diagnosis of lymphoma or cancer could be suspected by flow cytometry alone, while 4/16 were consistent with the final tissue diagnosis of normal or reactive hyperplasia. Three samples that came from patients who had morphologic evidence of malignant disease on biopsy (two Hodgkin's disease and one large cell lymphoma) had flow cytometry results that were interpreted as normal. Flow cytometry is rapid and appears to be virtually diagnostic of non-Hodgkin's lymphoma when a majority of cells are B cells with an abnormal kappa/lambda ratio (> 4.0 or < 0.25). Nonhematologic malignancy can be suspected if less than 75 percent of the cells show CD45 (common leukocyte antigen). Hodgkin's disease cannot be detected by flow cytometry as it is currently used, and as many as 15 percent (1/6 in this study) of lymphomas may show normal results. It is extremely helpful when the biopsy sample actually contains the cells of interest in large proportion. Loss of architectural relationships in the course of processing specimens for flow cytometry is a major disadvantage when small foci of lymphoma or tumor cells exist together with large amounts of stroma or normal lymphocytes.

Improving the diagnostic accuracy of cytologic cerebrospinal fluid examinations in acute lymphoblastic leukemia using high-power microscopy and terminal deoxynucleotidyl transferase determinations.

In patients with acute lymphoblastic leukemia (ALL), cytologic examination of cerebrospinal fluid (CSF) is becoming increasingly important for clinical management. In order to enhance the diagnostic accuracy of CSF cytology results, the value of using terminal deoxynucleotidyl transferase (Tdt) and high-power (1,000x) light microscopy, together with conventional cytologic examination was assessed. In 33 CSF samples from ten multiply examined Tdt-positive ALL patients, original cytologic interpretations were compared to Tdt results. Cytology samples were reviewed by two pathologists (one with hematopathologic expertise). The cases in which cytologic interpretation did not correlate with Tdt result were first reviewed via 1,000x microscopy without knowledge of Tdt result, then re-reviewed with knowledge of Tdt result. Conventional cytology alone diagnosed 64% of cases accurately (Tdt representing the comparative standard). High-power microscopy increased the correlation to 82%. Use of high-power microscopy and knowledge of Tdt result together produced a total of 85% of cases with correlation of results. High-power microscopic examination therefore contributes significantly to the accurate diagnosis of ALL, and knowledge of the Tdt result at the time of cytologic examination produces an additional advantage in providing an objective measure for CSF involvement by leukemia. Using all three methods in conjunction is recommended in order to increase the overall accuracy of CSF examination for the detection of leukemic involvement in ALL patients.

Factors influencing the selection of toys for handicapped and normally developing preschool children.

Factors influencing the selection and purchase of toys for children's use were investigated. Subjects were 73 parents or adult friends of normally developing or handicapped preschool children. In addition to providing demographic information about themselves, the subjects rated the importance of 17 factors influencing their selection and purchase of toys. Contrary to previous research, the sex of the child was reported to be of only minor importance in toy selection, as was the picture on the toy package. Two factors, safety and teaching new skills, were rated as extremely important. There were no significant differences in ratings as a result of sex, ethnicity, or whether or not the subjects were parents of a handicapped child. The findings suggest a substantial degree of agreement among parents about what they consider important when choosing toys for children.

A mouse caries model and evaluation of aqp5-/- knockout mice.

Current techniques to alter gene expression in mice allow direct analysis of the net role of a host factor in caries development. Towards this goal we first established protocols to induce and score caries in NFS/N mice and determined caries susceptibility in mice with targeted deletion of the gene encoding aquaporin-5 (Aqp5-/-), a water channel involved in the production of saliva. In the NFS/N strain of mice total sulcal caries and severity scores were consistent between experiments, whereas smooth surface caries scores were lower, more variable but distributed fairly evenly among the buccal, lingual and sulcal surfaces. In Black Swiss/129SvJ mice (genetic background of Aqp5-/- mice) caries scores were 50-75% lower compared to NFS/N mice, suggesting strain variation in caries susceptibility under our experimental conditions. In Aqp5-/- mice, in which the volume of total salivary secretion is reduced by 60-65%, there was a significant increase in caries, primarily on the buccal and sulcal surfaces. Results indicate that caries susceptibility increases with a reduced salivary flow that is associated with decreased water content of saliva.

Recovery from widespread bone marrow necrosis occurring after chemotherapy for adult acute monocytic leukemia.

A patient with acute monocytic leukemia who developed bone marrow necrosis following induction chemotherapy is presented. Although the bone marrow necrosis was extensive, recovery occurred, along with complete remission of leukemia. Severe bone marrow necrosis in this setting may be reversible, and continued vigorous supportive care for these patients should be strongly considered.

Low bone mineral density in hormone-naïve men with prostate carcinoma.

BACKGROUND: The objective of this study was to determine the prevalence of low bone mineral density in men with prostate carcinoma and no history of androgen-deprivation therapy. METHODS: The authors conducted a cross-sectional study in 41 hormone-naïve men with locally advanced, lymph node positive, or recurrent prostate carcinoma and no radiographic evidence of bone metastases. Bone mineral density of the total hip, posterior-anterior (PA) lumbar spine, and lateral lumbar spine was determined by dual-energy X-ray absorptiometry (DXA) using a densitometer. Trabecular bone mineral density of the lumbar spine was determined by quantitative computed tomography (QCT). Bone mineral density results were expressed in standard deviation units relative to young adult men (T score) and relative to age-matched men (Z score). RESULTS: Fourteen of 41 men (34%; 95% confidence interval [95% CI], 20-51%) had T scores < -1.0 at one or more skeletal sites by DXA, 12 of 41 men (29%; 95% CI, 16-42%) had T scores between -1.0 and -2.5, and 2 of 41 men (5%; 95% CI, 1-17%) had T scores < -2.5. Thirty-nine of 41 men (95%; 95% CI, 83-99%) had T scores < -1.0 by QCT, 13 of 41 men (31%; 95% CI 18-48%) had T scores between -1.0 and -2.5, and 26 of 41 men (63%; 95% CI, 47-78%) had T scores < -2.5. T scores for trabecular bone mineral density of the lumbar spine were significantly lower than T scores for either the total hip (P < 0.001) or the PA lumbar spine (P < 0.001). The mean Z score for trabecular bone mineral density of the lumbar spine was -0.7 +/- 0.9. Hypogonadism, hypovitaminosis D, and dietary calcium intakes below the Recommended Daily Allowance were observed in 20%, and 17%, and 59% of study participants, respectively. CONCLUSIONS: Many hormone-naïve men with prostate carcinoma have low bone mineral density. QCT is a more sensitive method than DXA for diagnosing low bone mineral density in this patient population. Trabecular bone mineral density is lower than expected for age and risk factors for osteoporosis are common.

Effects of photodynamic therapy on xenografts of human mesothelioma and rat mammary carcinoma in nude mice.

We have examined the effectiveness of photodynamic therapy against R3230AC rat mammary adenocarcinoma and human mesothelioma as xenografts in the same host. The results demonstrate that the xenografted human tumour is significantly more responsive to photodynamic treatment than the rodent mammary tumour. Studies also showed that the mesothelioma xenograft was fluence rate- and fluence-dependent while the rat tumour exposed to the same conditions demonstrated neither of these dependencies. This disparity in response was not attributable to a difference in either whole-tumour uptake or subcellular distribution of the porphyrin photosensitiser. Analysis of the effects of visible irradiation on cytochrome c oxidase activity, measured in mitochondria prepared from tumours borne on hosts injected with photosensitiser, demonstrated that photoradiation-induced enzyme inhibition was significantly greater in mesothelioma than in R3230AC mammary tumour preparations. However, in parallel studies conducted in vitro, when photosensitiser and light were delivered to previously unperturbed mitochondria, rates of enzyme inhibition were not significantly different. Both tumours were established in long-term cell culture. While the uptake of porphyrin photosensitiser was equivalent in both cell lines, the R3230AC cells displayed a significantly greater photosensitivity than the mesothelioma cells. The data presented here demonstrate that the mechanisms that govern response to photodynamic therapy are complex, but in the case of these two xenografted tumours host response to therapy is not likely to play a significant role.

In situ hybridization analysis of developmental stages of Pneumocystis carinii that are transcriptionally active for a major surface glycoprotein gene.

An abundant glycoprotein on the surface of Pneumocystis carinii, termed gpA or gp120, is thought to play a role in the interaction of this opportunistic pathogen with its host. Using RNA:RNA hybridization techniques, the in situ expression of gpA mRNA in developmental forms of the organism was investigated in a ferret model of P. carinii pneumonia. The results suggested that the relative abundance of gpA-specific mRNA was variable in different developmental stages of ferret P. carinii. P. carinii localized along the epithelial lining of alveoli were transcriptionally active. Immunocytochemical detection of gpA and Giemsa staining suggested that many of these organisms were trophic forms of P. carinii. While no detectable gpA mRNA signal was found in the majority of P. carinii cysts, a portion of identifiable cysts co-localized with significant levels of gpA mRNA signal. Differential staining of the cyst wall with Gomori's methenamine silver suggested that the transcriptionally active P. carinii cysts were the intermediate or precyst forms of the organism, while the cysts with no detectable mRNA signal were either mature or empty (excysted). Alveolar macrophages were observed surrounded by transcriptionally active organisms; however, no gpA-transcriptional activity was detected within macrophages. Taken together, the results suggest that transcription of gpA occurs in forms of P. carinii that are actively replicating, and in close proximity or contact with, alveolar epithelial cells.

Estrogen and progesterone receptor detection in archival formalin-fixed, paraffin-embedded tissue from breast carcinoma: a comparison of immunohistochemistry with the dextran-coated charcoal assay.

The steroid receptor (estrogen (ER) and progesterone receptor (PR] status was studied in 94 cases of invasive breast carcinoma from three separate institutions. All cases had fresh tissue examined for ER and PR by the dextran-coated charcoal cytosolic assay (DCC), and each case was examined immunohistochemically for ER and PR from archival formalin-fixed, paraffin-embedded tissue. Immunohistochemical assays (IH) were reviewed blinded to the DCC results and scored in a semiquantitative fashion prior to comparison to the DCC results. Overall, there was agreement between DCC and IH in 89% of ER and in 87% of PR assays. Some 50% of the ER discorrelations were of the IH-positive DCC-negative type, while 27% of the PR discorrelations were of this type. In four cases, both ER and PR did not correlate between IH and DCC determinations, with two being IH (ER and PR) positive and DCC negative, and two of the opposite type. The results of the study show that steroid receptor assays performed on routinely processed formalin-fixed archival material are reliable and closely recapitulate the results of traditional biochemical assays. Results suggest that, in the cases where IH is positive while DCC is negative, the IH result may actually provide a more reliable receptor status of the tumor than does the DCC result. Semiquantitation of fixed tissue IH assays shows a trend toward quantitative correlation with DCC results, but this correlation is weak, and factors concerning fixation and processing are most likely to be responsible.(ABSTRACT TRUNCATED AT 250 WORDS)

Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer.

BACKGROUND: Treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density and increases the risk of fracture in men with prostate cancer. We conducted a controlled study of the prevention of osteoporosis in men undergoing treatment with a gonadotropin-releasing hormone agonist. METHODS: In a 48-week, open-label study, we randomly assigned 47 men with advanced or recurrent prostate cancer and no bone metastases to receive either leuprolide alone or leuprolide and pamidronate (60 mg intravenously every 12 weeks). Bone mineral density of the lumbar spine and the proximal femur was measured by dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured by quantitative computed tomography. Forty-one men completed the study. RESULTS: In men treated with leuprolide alone, the mean (+/-SE) bone mineral density decreased by 3.3+/-0.7 percent in the lumbar spine, 2.1+/-0.6 percent in the trochanter, and 1.8+/-0.4 percent in the total hip, and the mean trabecular bone mineral density of the lumbar spine decreased by 8.5+/-1.8 percent (P<0.001 for each comparison with the base-line value). In contrast, the mean bone mineral density did not change significantly at any skeletal site in men treated with both leuprolide and pamidronate. There were significant differences between the two groups in the mean changes in bone mineral density at 48 weeks in the lumbar spine (P<0.001), trochanter (P = 0.003), total hip (P=0.005), and trabecular bone of the lumbar spine (P=0.02). CONCLUSIONS: Pamidronate prevents bone loss in the hip and lumbar spine in men receiving treatment for prostate cancer with a gonadotropin-releasing hormone agonist.

Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party.

BACKGROUND: The reverse-transcriptase inhibitor lamivudine has in vitro synergy with zidovudine against the human immunodeficiency virus (HIV). We studied the activity and safety of lamivudine plus zidovudine as compared with either drug alone as treatment for patients with HIV infection, most of whom had not previously received zidovudine. METHODS: Three hundred sixty-six patients with 200 to 500 CD4+ cells per cubic millimeter who had received zidovudine for four weeks or less were randomly assigned to treatment with one of four regimens: 300 mg of lamivudine every 12 hours; 200 mg of zidovudine every 8 hours; 150 mg of lamivudine every 12 hours plus zidovudine; or 300 mg of lamivudine every 12 hours plus zidovudine. The study was double-blind and lasted 24 weeks, with an extension phase for another 28 weeks. RESULTS: Over the 24-week period, the low-dose and high-dose regimens combining lamivudine and zidovudine were associated with greater increases in the CD4+ cell count (P = 0.002 and P = 0.015, respectively) and the percentage of CD4+ cells (P < 0.001 for both) and with greater decreases in plasma levels of HIV-1 RNA (P < 0.001 for both) than was treatment with zidovudine alone. Combination therapy was also more effective than lamivudine alone in lowering plasma HIV-1 RNA levels and increasing the percentage of CD4+ cells (P < 0.001 for all comparisons), and these advantages persisted through 52 weeks. Adverse events were no more frequent with combination therapy than with zidovudine alone. CONCLUSIONS: In HIV-infected patients with little or no prior antiretroviral therapy, treatment with a combination of lamivudine and zidovudine is well tolerated over a one-year period and produces more improvement in immunologic and virologic measures than does treatment with either agent alone.