Field trial to evaluate the effect of an intranasal respiratory vaccine protocol on calf health, ultrasonographic lung consolidation, and growth in Holstein dairy calves.

The objective of this field trial was to evaluate the effect of a vaccine protocol using a commercially available trivalent vaccine designed for intranasal use. Experimental challenge studies have demonstrated varying efficacies of vaccines administered via the intranasal route. A total of 468 calves from 3 herds were enrolled and randomized into 3 treatment groups (positive control, PC, n = 211; intranasal vaccine, IN, n = 215; negative control, NC, n = 42) and followed for 8 to 12 wk. The PC consisted of one dose of commercially available multivalent injectable vaccine against bovine respiratory syncytial virus, infectious bovine rhinotracheitis, parainfluenza 3, and bovine viral diarrhea administered subcutaneously at 6 wk of age. The IN was administered at enrollment and 6 wk of age, and contained antigen against bovine respiratory syncytial virus, infectious bovine rhinotracheitis, and parainfluenza 3. The NC was sterile saline administered intranasally and subcutaneously at enrollment and 6 wk of age. Clinical illness was assessed using systematic respiratory scoring, and thoracic ultrasonography was used to identify the lung consolidation associated with pneumonia. Rib fractures were identified in 6% of calves, and an association was observed between rib fractures and calving ease. Overall, 54% of the calves had at least one episode of an abnormal respiratory score (ILL). Vaccination protocol did not affect the occurrence of ILL. Similarly, 54% of the calves had at least one episode of lung consolidation ≥3 cm (CON). Vaccine protocol affected the odds of CON. The odds of CON in PC were 1.63 (95% confidence interval: 1.04-2.56) times the odds of CON in IN, and 0.38 (95% confidence interval: 0.16-0.93) times the odds of CON in NC. The odds of CON in IN were 0.23 (95% confidence interval: 0.09-0.59) times the odds of CON in NC. The outcomes ILL and CON were associated; however, the measure of agreement was only fair (kappa = 0.38). Multivariable linear regression revealed an interaction between vaccine protocol and herd on average daily gain (ADG); therefore, these data were stratified. In herd 1, IN (0.53 ± 0.03 kg/d) decreased ADG compared with PC (0.63 ± 0.03 kg/d). In herd 2, IN increased ADG (0.41 ± 0.03 kg/d) compared with PC (0.38 ± 0.03 kg/d). In contrast, none of the protocols affected ADG at herd 3. In conclusion, this commercially available trivalent IN vaccine protocol did not alter the incidence of ILL, reduced the risk of lung lesions associated with pneumonia, and improved the ADG of the calves in one of the commercial study herds.

Endometrial nitric oxide synthase activity in mares susceptible or resistant to persistent breeding-induced endometritis and the effect of a specific iNOS inhibitor in vitro.

Emerging research suggests that the nitric oxide system may play a role in persistent breeding-induced endometritis (PBIE) in the mare. Differences in uterine nitric oxide (NO) levels between mares susceptible or resistant to PBIE and a dose-dependent inhibitory effect of NO on uterine contractility have been demonstrated. The objectives of this study were to investigate the difference in total nitric oxide synthase (NOS) activity of the endometrium between susceptible and resistant mares and the effect of a specific inducible nitric oxide synthase (iNOS) inhibitor on the endometrial NOS activity in vitro. Six susceptible and six resistant mares were selected based on preset criteria and the results of an intrauterine challenge with killed spermatozoa during oestrus. Endometrial biopsy samples were collected 24 hr post-challenge and cultured at 37°C for 24 hr in L-arginine supplemented minimum essential medium with or without a specific iNOS inhibitor (1,400 W dihydrochloride, 1 mM). The medium and the cultured endometrial tissue were collected after 24 hr of culture and assayed for NO and total protein, respectively. Total NO content of the medium, normalized to endometrial tissue wet weight or total protein, was used as a measure of endometrial NOS activity. Non-parametric tests were applied for statistical analysis. Susceptible mares had significantly greater endometrial NOS activity than resistant mares. The iNOS inhibitor treatment significantly reduced NOS activity in endometrial samples derived from susceptible and resistant mares. These findings provide a basis for in vivo testing of specific iNOS inhibitors as preventative or therapeutic options for PBIE in mares.

Survey of Equine Referring Veterinarians' Satisfaction with Their Most Recent Equine Referral Experience.

BACKGROUND: Little is known about the veterinary referral process and factors that contribute to positive outcomes. OBJECTIVE: To investigate equine referring veterinarians' (rDVMs') satisfaction with their most recent referral experience and compare rDVM and specialist perspectives. SAMPLE: 187 rDVMs and 92 specialists (referral care providers). METHODS: Cross-sectional observational study. An online survey was administered to both rDVMs and specialists. Referring veterinarian satisfaction with their most recent referral experience was evaluated. Both rDVMs and specialists were asked to identify factors influencing a rDVM's decision where to refer, and the top 3 factors they perceive are barriers to referral care. RESULTS: Median rDVM satisfaction with their most recent referral care experience was 80 of 100 (mean, 75; range, 8-100). Referring veterinarians provided the lowest satisfaction score for the item asking about "The competition the referral hospital poses to your practice" (mean, 56.96; median, 62; range, 0-100). The top factor rDVMs identified as influencing their decision where to refer was "quality of care," whereas specialists identified "quality of communication and updates from the clinician." Referring veterinarians' top barrier to referral care was "high cost of referral care," and for specialists was "poor service provided to the client by the referral hospital." CONCLUSIONS AND CLINICAL IMPORTANCE: Referring veterinarians generally were satisfied with referral care, but areas exist where rDVMs and specialists differ in what they view as important to the referral process. Exploring opportunities to overcome these differences is likely to support high quality care.

Proceedings of the First Workshop Organized by the IAFSS Working Group on Measurement and Computation of Fire Phenomena (MaCFP).

This paper provides a report of the discussions held at the first workshop on Measurement and Computation of Fire Phenomena (MaCFP) on June 10-11 2017. The first MaCFP work-shop was both a technical meeting for the gas phase subgroup and a planning meeting for the condensed phase subgroup. The gas phase subgroup reported on a first suite of experimental- computational comparisons corresponding to an initial list of target experiments. The initial list of target experiments identifies a series of benchmark configurations with databases deemed suitable for validation of fire models based on a Computational Fluid Dynamics approach. The simulations presented at the first MaCFP workshop feature fine grid resolution at the millimeter- or centimeter- scale: these simulations allow an evaluation of the performance of fire models under high-resolution conditions in which the impact of numerical errors is reduced and many of the discrepancies between experimental data and computational results may be attributed to modeling errors. The experimental-computational comparisons are archived on the MaCFP repository [1]. Furthermore, the condensed phase subgroup presented a review of the main issues associated with measurements and modeling of pyrolysis phenomena. Overall, the first workshop provided an illustration of the potential of MaCFP in providing a response to the general need for greater levels of integration and coordination in fire research, and specifically to the particular needs of model validation.

Systematic Review of the Diagnostic Accuracy of Haptoglobin, Serum Amyloid A, and Fibrinogen versus Clinical Reference Standards for the Diagnosis of Bovine Respiratory Disease.

BACKGROUND: Bovine respiratory disease (BRD) is a worldwide animal health concern especially in feedlot, dairy, and veal calves. One of the greatest challenges is the absence of a gold standard for achieving an accurate antemortem diagnosis. Various blood markers, including the acute-phase proteins (AAP), have been proposed as potential valuable tools for BRD diagnosis. OBJECTIVES: To perform a systematic review of the literature to assess the accuracy of selected APP (haptoglobin [Hp], serum amyloid A [SAA], and fibrinogen [Fb]) as diagnostic tools for cattle with naturally occurring BRD when compared with clinical reference standards of diagnosis. METHODS: This review was performed with eligible studies selected from CAB Abstract and MEDLINE from 1946 to 2015, as well as the "gray literature." Methodological quality of included studies was assessed using the QUADAS-2 tool developed for diagnostic accuracy studies. The accuracy parameters sensitivity (Se) and specificity (Sp) were obtained from the articles or through contact with the authors when not directly reported. RESULTS: A total of 314 studies were identified, from them, 23 met inclusion criteria as diagnostic studies for naturally occurring BRD. Quality of studies showed high risk of bias for case selection (70% of articles) and unclear risk of bias for index test (65%), reference standard (74%), and flow and timing (61%). There were high concerns regarding applicability for case selection (61% of studies) and reference standards used for defining BRD (48%). The concerns regarding index test application were low (83% of the studies). Only 4-8 studies could be included in the meta-analysis for each APP. No pooled estimates or pooled accuracy measurements were performed due to the low number of studies and multiple differences between studies, including reference standard definitions. CONCLUSIONS AND CLINICAL IMPORTANCE: On the basis of these findings, it is not possible to make conclusions regarding the accuracy of APP for BRD diagnosis. The reporting of accuracy of APP for BRD detection is inconsistent among studies. Recommendations to improve capability for future meta-analyses in this area include reporting studies on diagnostic tests following the Standard for the Reporting of Diagnostic Accuracy Studies (STARD), as well as trying to standardize BRD definition across future studies.

Thoracic Ultrasonography and Bronchoalveolar Lavage Fluid Analysis in Holstein Calves with Subclinical Lung Lesions.

BACKGROUND: Thoracic ultrasonography (US) and bronchoalveolar lavage fluid (BALF) analysis are antemortem methods used to identify the lung lesions associated with bovine respiratory disease (BRD). Accuracy of US and the cell distributions in BALF have not been characterized in calves with subclinical disease. OBJECTIVES: To evaluate the accuracy of US and BALF and describe BALF characteristics in calves with subclinical lung lesions. ANIMALS: Twenty-five Holstein calves, 1-12 weeks old. METHODS: In this prospective study, calves with low respiratory scores underwent US, BALF and postmortem examination (normal US, n = 5; comet-tails, n = 5; consolidation, n = 15). Bronchoalveolar lavage fluid was collected and analyzed for total and differential cell counts. Lung lesions were assessed by gross and histopathologic examination. Data were analyzed using nonparametric methods and relative risk analysis. The accuracy of US and BALF were estimated relative to postmortem examination. RESULTS: The sensitivity and specificity of US for detecting lung lesions was 94% (95% CI, 69-100%) and 100% (95% CI, 64-100%), respectively. A cut-point of ≥4% BALF neutrophils was associated with the highest BALF sensitivity and specificity, 81% (95% CI, 56-94%) and 75% (95% CI, 36-95%). The presence of consolidation on US increased the risk of having a BALF neutrophil proportion ≥4% (RR, 3.9; 95% CI, 1.13-13.45; P = .003). CONCLUSIONS AND CLINICAL IMPORTANCE: Ultrasonography accurately detects lung lesions in calves with subclinical disease. Clinicians should use a cut-point of ≥4% BALF neutrophils to diagnose subclinical respiratory disease.

Comparison of continuous infusion with intermittent bolus administration of cefotaxime on blood and cavity fluid drug concentrations in neonatal foals.

Healthy neonatal foals were treated with cefotaxime by bolus (40 mg/kg i.v. q6h for 12 doses; n=10) or by infusion (loading dose of 40 mg/kg i.v. followed by continuous infusion of a total daily dose of 160 mg/kg per 24 h for 3 days; n=5). Population pharmacokinetics was determined, and concentrations in cavity fluids were measured at steady state (72 h). Highest measured serum drug concentration in the bolus group was 88.09 µg/mL and minimum drug concentration (C(min)) was 0.78 µg/mL at 6-h postadministration (immediately before each next dose), whereas infusion resulted in a steady-state concentration of 16.10 µg/mL in the infusion group. Mean cefotaxime concentration in joint fluid at 72 h was higher (P=0.051) in the infusion group (5.02 µg/mL) compared to the bolus group (0.78 µg/mL). Drug concentration in CSF at 72 h was not different between groups (P=0.243) and was substantially lower than serum concentrations in either group. Insufficient data on pulmonary epithelial lining fluid were available to compare the methods of administration for cefotaxime in this cavity fluid. Results support continuous drug infusion over bolus dosing in the treatment for neonatal foal septicemia to optimize time that cefotaxime concentration exceeds the minimum inhibitory concentration of common equine pathogens.

Gelatinous marrow transformation and hematopoietic atrophy in a miniature horse stallion.

Gelatinous marrow transformation, or serous atrophy of bone marrow fat, has been noted in livestock, laboratory animals, and wildlife in association with an inadequate plane of nutrition, inanition, or intoxication. This is a report of gelatinous marrow transformation and hematopoietic marrow atrophy in a 5-year-old miniature horse stallion. The horse had oral malformations leading to poor food assimilation and emaciation. A bone marrow biopsy obtained to investigate persistent anemia and leukopenia showed hematopoietic atrophy and replacement of fat with a granular extracellular substance, which stained with alcian blue, consistent with acidic mucopolysaccharide content. Surgical correction of the dental abnormalities resulted in improved food assimilation, weight gain, and resolution of cytopenias. In humans, gelatinous bone marrow transformation and hematopoietic atrophy are commonly associated with malnutrition from anorexia nervosa and other causes. The cause of hematopoietic atrophy is unknown but may relate to a nonsupportive marrow microenvironment and inadequate hematopoietic substrate availability. Similar pathogenic mechanisms were suspected in this horse.

The power of bioenergy-related standards to protect biodiversity.

The sustainable production of bioenergy is vital to avoiding negative impacts on environmental goods such as climate, soil, water, and especially biodiversity. We propose three key issues that should be addressed in any biodiversity risk-mitigation strategy: conservation of areas of significant biodiversity value; mitigation of negative effects related to indirect land-use change; and promotion of agricultural practices with few negative impacts on biodiversity. Focusing on biodiversity concerns, we compared principles and criteria set to address biodiversity and other environmental and social issues in seven standards (defined here as commodity-based standards or roundtables, or relevant European legislation): five voluntary initiatives related to bioenergy feedstocks, the Renewable Transport Fuel Obligation (United Kingdom), and the European Renewable Energy Source Directive. Conservation of areas of significant biodiversity value was fairly well covered by these standards. Nevertheless, mitigation of negative impacts related to indirect land-use change was underrepresented. Although the EU directive, with its bonus system for the use of degraded land and a subquota system for noncrop biofuels, offered the most robust standards to mitigate potential negative effects, all of the standards fell short in promoting agricultural practices with low negative impacts on biodiversity. We strongly recommend that each standard be benchmarked against related standards, as we have done here, and that efforts should be made to strengthen the elements that are weak or missing. This would be a significant step toward achieving a bioenergy industry that safeguards Earth's living heritage.

Retrospective study of the clinical features of limb cellulitis in 63 horses.

A retrospective study of 63 horses diagnosed with limb cellulitis between 1994 and 2005 was conducted. They all had an acute onset of painful, generalised limb swelling, and a clinical diagnosis of limb cellulitis was made by the attending clinician. None of the horses had more than one limb affected. Hindlimbs were significantly more often affected than the forelimbs (P<0.05). Thoroughbreds were significantly over-represented compared with the general distribution of breeds examined at the hospital. Blunt limb trauma, limb surgery and limb injections were associated with the cellulitis in most of the horses, but no plausible cause could be determined in 27 (43 per cent) of the cases. Staphylococcus aureus and Streptococcus species were frequently isolated, although mixed bacterial infections were also common. All the horses were treated with broad spectrum antimicrobials and non-steroidal anti-inflammatory agents, and ultrasound-guided surgical drainage was also applied in 14 cases. Fifty-six of the 63 horses (89 per cent) were discharged from the hospital. Laminitis affecting the contralateral limb was the most common reason for the euthanasia of the other seven horses.

CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment.

The role of CXCL12 in the bone marrow (BM) homing and growth of B-cell progenitor acute lymphoblastic leukemia (ALL) has been established. However, the effect of modulating CXCL12/CXCR4 interactions on the retention of ALL cells within the supportive BM microenvironment and the expansion and dissemination of ALL cells in vivo has not been examined. We used mouse models of human childhood and murine leukemia and specific peptide and small molecule CXCR4 antagonists to examine the importance of CXCL12/CXCR4 in the development of leukemia in vivo. CXCR4 antagonists mobilized ALL cells into the peripheral blood (PB). Extended administration of CXCR4 antagonists to mice with leukemia resulted in a reduction in the number of leukemic cells in the PB and spleens of animals compared to control treated animals in three of the five cases tested. There was also a marked reduction in the dissemination of ALL cells to extramedullary sites including liver and kidney in all cases where this occurred. Considering the inhibitory effect of stromal layers on the activity of chemotherapeutic agents and the interactive effect of CXCL12 antagonists with chemotherapeutic agents in vitro, this raises the possibility of using these agents to potentiate the effects of current chemotherapy regimens.

Peritonitis in a llama caused by Streptococcus equi subsp. zooepidemicus.

A 7-month-old, male llama was diagnosed with peritonitis caused by Streptococcus equi subsp. zooepidemicus. Clinical findings, medical treatment, and case outcome are described. Hematogenous dissemination from suspected pneumonia is proposed as the route of infection in this case. Possible transmission of the organism through contact with horses is discussed.

Effects of the chemokine stromal cell-derived factor-1 on the migration and localization of precursor-B acute lymphoblastic leukemia cells within bone marrow stromal layers.

Acute lymphoblastic leukemia (ALL) blasts undergo migration into layers of bone marrow fibroblasts (BMF) in vitro, utilizing the beta1 integrins VLA-4 and VL-5 as adhesion molecules. However, it has been unclear as to whether this is a selective process mediated by specific chemoattractant molecules, or simply a reflection of the highly motile nature of early B cell precursors. We further characterized this process using a transwell culture system, in which the two chambers were separated by an 8 microm diameter microporous membrane, through which leukemic cells could move. When a BMF layer was grown on the upper surface of the membrane there was an 84.1% reduction in transmigration of the human pre-B ALL cell line NALM-6 into the lower chamber, compared to control membrane with no BMF layer. Localization of leukemic cells under the BMF layer was confirmed ultrastructurally, suggesting the possibility that the migration of leukemic cells was directed by a chemotactic agent secreted by BMF. The involvement of the chemokine stromal cell-derived factor-1 (SDF-1) in this process was next investigated. BMF were shown to express m-RNA for SDF-1. Addition of SDF-1 at 100 ng/ml into the lower chamber increased transmigration of NALM-6 across the membrane by 2.2-fold, and also induced a 1.4- to 6.1-fold increase in movement of NALM-6 through a BMF layer into the lower chamber. The receptor for SDF-1, CXCR4, was demonstrated by flow cytometry on all 10 cases of precursor-B ALL analyzed, as well as on NALM-6, KM-3 and REH lines. An inhibitory antibody to CXCR4 was able to block the migration of NALM-6 cells into BMF monolayers grown on plastic by 51%, and in nine cases of ALL by 8-40%, as well as partially inhibit transmigration of leukemic cells through BMF layers along an SDF-1 concentration gradient. These results confirm that precursor-B ALL cells selectively localize within bone marrow stroma in vitro, and that this process is partially due to the stromal chemokine SDF-1 binding to its receptor CXCR4 on leukemic cells. SDF-1 may be important in influencing the localization of precursor-B ALL cells in marrow microenvironmental inches which regulate their survival and proliferation.

Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis.

Neural stem cells in the lateral ventricles of the adult mouse CNS participate in repopulation of forebrain structures in vivo and are amenable to in vitro expansion by epidermal growth factor (EGF). There have been no reports of stem cells in more caudal brain regions or in the spinal cord of adult mammals. In this study we found that although ineffective alone, EGF and basic fibroblast growth factor (bFGF) cooperated to induce the proliferation, self-renewal, and expansion of neural stem cells isolated from the adult mouse thoracic spinal cord. The proliferating stem cells, in both primary culture and secondary expanded clones, formed spheres of undifferentiated cells that were induced to differentiate into neurons, astrocytes, and oligodendrocytes. Neural stem cells, whose proliferation was dependent on EGF+bFGF, were also isolated from the lumbar/sacral segment of the spinal cord as well as the third and fourth ventricles (but not adjacent brain parenchyma). Although all of the stem cells examined were similarly multipotent and expandable, quantitative analyses demonstrated that the lateral ventricles (EGF-dependent) and lumbar/sacral spinal cord (EGF+bFGF-dependent) yielded the greatest number of these cells. Thus, the spinal cord and the entire ventricular neuroaxis of the adult mammalian CNS contain multipotent stem cells, present at variable frequency and with unique in vitro activation requirements.

Ultrastructural changes during adhesion and migration of pre-B lymphoid leukaemia cells within bone marrow stroma.

The ultrastructural changes in leukaemic cells on initial contact with, and during migration into, layers of bone marrow stroma in vitro were examined in a variety of types of acute leukaemia and leukaemic cell lines. Bone marrow fibroblasts (BMF) were grown on polycarbonate microporous membranes, and acute leukaemia cells added to cultures and allowed to adhere to BMF for variable periods of time before fixation. Acute lymphoblastic leukaemia (ALL) blasts showed rapid development of surface membrane microvilli on contact with BMF layers. ALL blasts, and the pre-B ALL cell line NALM-6, showed evidence of movement in to the BMF layer within 15-30 min, with intrusion of extended cytoplasic processes into gaps between BMF cytoplasm. ALL cells were frequently seen within the layers of fibroblasts after 30 min incubation, and had pronounced morphological changes, with pseudopodia and attenuated and elongated microvilli interdigitating with the surface of fibroblasts or with strands of extracellular matrix material. Changes were also noted in the surface membrane of BMF adjacent to ALL cells, with invagination of the cytoplasmic membrane and formation of micropits. In contrast to the migratory behaviour of pre-B ALL cells, migration was not observed with acute myeloid leukaemia cells or other leukaemic cell lines. These cells showed membrane activation, with variable degrees of microvillous formation, and in some cases insertion of pseudopodia into BMF layers, but migration was not observed. Ultrastructural immunogold labelling was carried out to determine the localization of leukaemic adhesion molecules and their ligands on BMF. This demonstrated that beta 1 integrins were largely localized to the contact surfaces of both ALL blasts and fibroblasts, with VCAM-1 expressed only on the surface of BMF. These observations confirm the specificity of migratory behaviour for pre-B leukaemic cells, and indicate that a complex pattern of surface and intracellular events mediate this process, including the expression of beta 1 integrins and VCAM-1 at the sites of insertion of leukaemic cells between fibroblast margins.

The myelodysplastic syndromes: an analysis of prognostic factors in 226 cases from a single institution.

Two hundred and twenty-six patients were diagnosed with myelodysplastic syndrome (MDS), according to the French-American-British (FAB) criteria, over a 13-year period, and studied retrospectively in a single institution in order to study indicators which were prognostically significant. Analysis of clinical and laboratory data indicated that the FAB classification, the Bournemouth, Dusseldorf, Goasguen, Sanz and FAB Scoring Systems were all good predictors of survival. We found advancing age, haemoglobin (Hb) < or = 9 g/dl, platelet count < or = 50 x 10(9)/l, increased peripheral total white cell count (WCC) and monocytosis, increased bone marrow blasts, dysgranulopoiesis, and bone marrow fibrosis were significant adverse prognostic variables. The commonest complication and cause of death was infection; however, infective episodes were not significantly associated with low neutrophil counts (either < or = 1.5 x 10(9)/l or < or = 0.8 x 10(9)/l) and there was also no significant association between neutropenia and survival. These findings indicate that neutrophil dysfunction plays an important role in the clinical progression of patients with MDS. The effect of new therapeutic modalities, such as the haemopoietic growth factors, on reducing infective episodes may be as significant as their effect on increasing neutrophil counts.

Migration of acute lymphoblastic leukemia cells into human bone marrow stroma.

Most cases of acute lymphoblastic leukemia (ALL) arise from malignant transformation of B-cell precursors in the bone marrow. Recent studies have shown that normal and leukemic B-cell precursors bind to bone marrow stromal cells through the beta-1 integrins VLA-4 and VLA-5, thereby exposing early lymphoid cells to regulatory cytokines. It has been recently reported that the pre-B cell line NALM-6 is capable of migrating under layers of murine stromal cells in vitro (Miyake et al. J Cell Biol 1992;119:653-662). We have further analyzed leukemic cell motility using human bone marrow fibroblasts (BMF) as a stromal layer. The precursor-B ALL cell line NALM-6 rapidly adhered to BMF, and underwent migration or tunneling into BMF layers within 5 h, as demonstrated by light and electron microscopy, and confirmed by a chromium-labeling assay. Migration was also observed with the precursor-B ALL lines Reh and KM-3, with a T leukemia line RPMI-8402, the monocytic line U937, and the mature B line Daudi. In contrast, mature B (Raji), myeloid (K562, HL-60), and T lines (CCRF-CEM, MOLT-4) did not migrate. When cases of leukemia were analyzed, BMF migration was largely confined to precursor-B ALL, occurring in eight of 13 cases tested. Of other types of leukemia, migration was observed in one of four cases of T-ALL, but no evidence was seen in six acute myeloid leukemias and two patients with chronic lymphocytic leukemia. Only minimal migration into BMF was observed with purified sorted CD10+ CD19+ early B cells from normal adult marrow, while normal mature B lymphocytes from peripheral blood did not migrate. ALL migration was inhibited by monoclonal antibodies to the beta sub-unit of the VLA integrin family, and by a combination of antibodies to VLA-4 and VLA-5. Partial inhibition was also observed when leukemic cells were incubated with antibodies to VLA-4, VLA-5, or VLA-6 alone. In contrast, treatment of stromal cells with antibodies to vascular cell adhesion molecule or fibronectin (ligands of VLA-4 and VLA-5) did not prevent leukemic cell migration. These results indicate that ALL cells are highly motile and capable of rapid migration within marrow stroma, an effect largely mediated by VLA-4 and VLA-5. In the case of precursor-B ALL, this process may reflect a homing mechanism to areas of selective growth advantage within the bone marrow microenvironment.