Tolerability of MenACWY-TT vaccination in adolescents in the Netherlands; a cross-sectional study.

BACKGROUND: In 2018, meningococcal ACWY-TT vaccine (MenACWY-TT) was offered to adolescents in the Netherlands within the National Immunization Programme at 14 years of age. A questionnaire study assessed the tolerability of this vaccine. METHODS: Five thousand adolescents were invited to participate and to fill in two questionnaires about systemic events in the week before vaccination and local reactions and systemic events in the week after vaccination. Frequencies of local and systemic adverse events in the week after vaccination were calculated. Association between the occurrence of systemic symptoms in the week before and after the vaccination was tested by using generalized mixed models (GLMM). RESULTS: Of all adolescents, 139 returned one or both questionnaires. Any local reaction within 7 days after vaccination was reported by 55.6% of the adolescents. Pain (50%) and reduced use of the injected arm (21.3%) were most often reported. Any systemic event was reported by 67.6% of the participants, with myalgia as the most often reported event (37.0%). Compared with the week before vaccination, there were no increased odds of experiencing systemic symptoms in the week after vaccination (OR 0.95; 95%CI 0.40-2.27). CONCLUSIONS: After vaccination with MenACWY-TT vaccine, most adolescents reported one or more adverse events, which were mostly mild and transient. Systemic symptoms were not reported more often in the week after compared to the week before vaccination. Unfortunately, due to a low response rate we were not able to detect the absolute elevated risks the sample size calculation was based on. However, despite limited data, our results are in line with results from prelicensure data, and indicate that MenACWY-TT vaccination is well tolerated in adolescents.

Faecal carriage, risk factors, acquisition and persistence of ESBL-producing Enterobacteriaceae in dogs and cats and co-carriage with humans belonging to the same household.

BACKGROUND: ESBL-producing Enterobacteriaceae (ESBL-E) are observed in many reservoirs. Pets might play an important role in the dissemination of ESBL-E to humans since they live closely together. OBJECTIVES: To identify prevalence, risk factors, molecular characteristics, persistence and acquisition of ESBL-E in dogs and cats, and co-carriage in human-pet pairs belonging to the same household. METHODS: In a nationwide study, one person per household was randomly invited to complete a questionnaire and to submit a faecal sample. Dog and cat owners were invited to also submit a faecal sample from their pet. Repeated sampling after 1 and 6 months was performed in a subset. ESBL-E were obtained through selective culture and characterized by WGS. Logistic regression analyses and random forest models were performed to identify risk factors. RESULTS: The prevalence of ESBL-E carriage in these cohorts was 3.8% (95% CI: 2.7%-5.4%) for human participants (n=550), 10.7% (95% CI: 8.3%-13.7%) for dogs (n=555) and 1.4% (95% CI: 0.5%-3.8%) for cats (n=285). Among animals, blaCTX-M-1 was most abundant, followed by blaCTX-M-15. In dogs, persistence of carriage was 57.1% at 1 month and 42.9% at 6 months. Eating raw meat [OR: 8.8, 95% CI: 4.7-16.4; population attributable risk (PAR): 46.5%, 95% CI: 41.3%-49.3%] and dry food (OR: 0.2, 95% CI: 0.1-0.5; PAR: 56.5%, 95% CI: 33.2%-66.6%) were predictors for ESBL-E carriage in dogs. Human-dog co-carriage was demonstrated in five households. Human-cat co-carriage was not observed. CONCLUSIONS: ESBL-E prevalence was higher in dogs than in humans and lowest in cats. The main risk factor for ESBL-E carriage was eating raw meat. Co-carriage in dogs and household members was uncommon.

Away from home meals: associations with biomarkers of chronic disease and dietary intake in American adults, NHANES 2005-2010.

BACKGROUND: Away from home (AFH) meals are known to be energy-dense and of poor diet quality. Both direct and indirect exposure (for example, neighborhood restaurant density) to AFH meals have been implicated as contributors to higher body weight and adverse health outcomes. OBJECTIVE: To examine the association of frequency of eating AFH and fast-food meals with biomarkers of chronic disease and dietary intake. DESIGN: This cross-sectional study used frequency of AFH and fast-food meal and biomarker data from the NHANES 2005-2010. Information on weekly frequency of AFH and fast-food meals was collected via questionnaire during the household interview. The metabolic biomarkers examined included body mass index (BMI), serum cholesterol (total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL)), triglycerides, glycohemoglobin and fasting glucose (n=8314, age⩾20, National Health and Nutrition Examination Surveys (NHANES) 2007-2010). Biomarkers of dietary exposure included serum concentrations of vitamins A, D, E, C, B-6, B-12, folate and carotenoids (n=4162; 2005-2006). Multiple linear and logistic regression methods adjusted for complex survey methodology and covariates. RESULTS: American adults reported a mean of 3.9 (95% confidence interval 3.7, 4.0) AFH and 1.8 (1.6, 1.9) fast-food meals/week. Over 50% of adults reported ⩾3 AFH and >35% reported ⩾2 fast-food meals/week. The mean BMI of more frequent AFH or fast-food meal reporters was higher (Ptrend⩽0.0004). Serum concentrations of total, LDL and HDL-cholesterol were related inversely with frequency of AFH meals (P<0.05). Frequencies of fast-food meals and serum HDL-cholesterol were also related inversely (P=0.0001). Serum concentrations of all examined micronutrients (except vitamin A and lycopene) declined with increasing frequency of AFH meals (P<0.05); women and ⩾50-year olds were at higher risk. CONCLUSIONS: Reporters of frequent AFH and fast-food meals had higher BMI and lower concentrations of HDL-cholesterol; however, profiles of other biomarkers did not indicate higher metabolic risk. However, the serum concentrations of nutrients with mostly plant foods as sources declined with increasing AFH meal frequency.

Reflections after the Diane affair.

The Pharmacovigilance Centre Lareb received 621 reports of possible adverse drugs reactions on Diane-35® . Of all reports, 388 were received after media attention. Of the 309 reports of thromboembolic adverse drugs reactions, 18 cases were fatal. In 31 cases the thromboembolic adverse drugs reaction was initially not recognized as such. The analysis and the turmoil of the 'Diane affair' gave rise to the following reflections: Reflection 1. Continuous awareness and attention of risk of medicines is needed, also for known risks, for timely recognition of adverse drugs reactions. Reflection 2. Reporting side effects should be part of the professional attitude. Reports play a pivotal role in the detection of new adverse drugs reactions and the conditions under which known adverse drugs reactions occur. Reflection 3. Improvement of adequate use of drugs. Pharmacovigilance not only has the aim to improve knowledge on risk of medicines, but also the aim of getting this knowledge into Health Care practice.

A bead-based suspension array for the serological detection of Trichinella in pigs.

The feasibility of using bead-based suspension arrays to detect serological evidence of Trichinella in pigs was assessed. Trichinella spiralis excretory-secretory antigen was covalently coupled to paramagnetic beads and used to bind serum antibodies, which were subsequently detected using anti-swine antibody. The assay was evaluated by testing pig sera from farms where trichinellosis was endemic and comparing the results with those obtained using two commercially available ELISAs. With cut-offs established by receiver operating characteristic (ROC) analysis, digestion-negative sera from a Trichinella-free population of pigs were deemed seronegative. When anti-swine antibody was replaced with protein A/G, higher test sensitivity (94% vs. 88%) at similar test specificity (95%), was achieved. The potential use of this assay in species other than swine was also demonstrated by testing human sera.

Occurrence and characteristics of extended-spectrum-ß-lactamase- and AmpC-producing clinical isolates derived from companion animals and horses.

OBJECTIVES: To investigate the occurrence and characteristics of extended-spectrum ß-lactamase (ESBL)- and AmpC-producing Enterobacteriaceae isolates in clinical samples of companion animals and horses and compare the results with ESBL/AmpC-producing isolates described in humans. METHODS: Between October 2007 and August 2009, 2700 Enterobacteriaceae derived from clinical infections in companion animals and horses were collected. Isolates displaying inhibition zones of ≤ 25 mm for ceftiofur and/or cefquinome by disc diffusion were included. ESBL/AmpC production was confirmed by combination disc tests. The presence of resistance genes was identified by microarray, PCR and sequencing, Escherichia coli genotypes by multilocus sequence typing and antimicrobial susceptibility by broth microdilution. RESULTS: Sixty-five isolates from dogs (n = 38), cats (n = 14), horses (n = 12) and a turtle were included. Six Enterobacteriaceae species were observed, mostly derived from urinary tract infections (n = 32). All except 10 isolates tested resistant to cefotaxime and ceftazidime by broth microdilution using clinical breakpoints. ESBL/AmpC genes observed were bla(CTX-M-1, -2, -9, -14, -15,) bla(TEM-52), bla(CMY-2) and bla(CMY-)(39). bla(CTX-M-1) was predominant (n = 17). bla(CTX-M-9) occurred in combination with qnrA1 in 3 of the 11 Enterobacter cloacae isolates. Twenty-eight different E. coli sequence types (STs) were found. E. coli carrying bla(CTX-M-1) belonged to 13 STs of which 3 were previously described in Dutch poultry and patients. CONCLUSIONS: This is the first study among a large collection of Dutch companion animals and horses characterizing ESBL/AmpC-producing isolates. A similarity in resistance genes and E. coli STs among these isolates and isolates from Dutch poultry and humans may suggest exchange of resistance between different reservoirs.

[A free market is unfavourable for health care]. / Marktwerking is niet gunstig voor de gezondheidszorg.

The new health care system in the Netherlands introduces a free market into the health care sector. Because health care lacks some essential conditions, a free market will not provide effective resource allocation in this sector. In addition, a free market leads to more bureaucracy and less solidarity, cooperation and freedom of choice. It also impairs the autonomy of the medical professional.

The relation of the pleural thickening in tuberculosis pleurisy with the activity of adenosine deaminase.

BACKGROUND: Residual pleural thickening (RPT) still occurs in most patients with tuberculosis pleurisy despite advances in the treatment of tuberculosis. The aim of this study was to evaluate the significance of RPT in tuberculosis pleurisy with the patients clinical findings, biochemical and microbiological properties of pleural effusion and with the total adenosine deaminase (ADA) and isoenzymes levels. METHODS: 121 tuberculosis pleurisy patients were evaluated retrospectively. According to posteroanterior chest x-rays, the 63 (52%) cases with the thickness 2 mm or more in lower lateral hemithorax were grouped as I and the 58 (48%) cases without pleural thickness were grouped as II. The amount of pleural effusion was classified into small, medium or massive according to their chest x-rays. In both groups; sex, age, symptoms score, bacteriological and biochemical tests and ADA levels were recorded. RESULTS: 81 (67%) male and 40 (33%) female, overall 121 patients were enrolled into the study. RPT was found higher in males (p=0.014) and the increase ran parallel with the amount of cigarette smoking (p=0.014). RPT was found to be lower in small effusions (p=0.001). The group with RPT, the serum albumin was found lower (p=0.002), pleural fluid total protein (p=0.047) and the ratio of pleural fluid protein to serum protein (p=0.002) were found higher. In group I, total ADA: 69.5 +/- 38.9 IU/L and ADA2: 41.3 +/- 31.6 IU/L were higher than the cases without RPT (p=0.032, p=0.017, respectively). CONCLUSIONS: We suggest that the immunological mechanisms are effective in the development of pleural thickening.

Energy density of diets reported by American adults: association with food group intake, nutrient intake, and body weight.

OBJECTIVE: Recent reports suggest that dietary energy density may play a role in regulation of food intake. However, little is known about the energy density of diets consumed by free-living populations; therefore, the purpose of this study was to examine demographic, health, and nutritional correlates of energy density of self-reported diets. RESEARCH METHODS AND PROCEDURES: Using data from the NHANES III (n=13 400), dietary energy density was defined three ways: (1) energy content (kJ/g) of all foods and beverages reported or ED1, (2) energy content (kJ/g) of all foods and energy yielding beverages or ED2, and (3) energy content (kJ/g) of all foods (no beverages) or ED3. Multiple linear or logistic regression methods were used to examine the association of energy density with intake of energy, nutrients, food groups, and body mass index (BMI). We computed the ratios of within- to between-person variance for the three energy density variables using the second recall obtained from the second exam subsample of NHANES III (n=1037). RESULTS: The mean ED1, ED2, and ED3, respectively, were 3.84+/-0.02, 5.45+/-0.03, and 8.03+/-0.03. Dietary intakes of energy, fat, and low-nutrient-density foods were related positively, but amounts of micronutrients, fruit, and vegetables were related inversely with all types of energy density (P<0.0001). ED2 and ED3 were modest positive predictors of BMI in both men and women (P< or =0.03). The ratios of within- to between-person components of variance for ED1, ED2, and ED3 were 1.34, 2.05, and 1.53, respectively. DISCUSSION: High-energy-density diets in the US were characterized by low fruit and vegetable intake, and high BMI.

Interaction of body mass index and attempt to lose weight in a national sample of US adults: association with reported food and nutrient intake, and biomarkers.

OBJECTIVE: This study examined the interaction between body mass index (BMI) and attempting to lose weight for reporting of: (1) macro- and micronutrient intake; (2) intake of low-nutrient-density foods; and (3) serum biomarkers of dietary exposure and cardiovascular disease risk. METHODS: Dietary, anthropometric and biochemical data were from the third National Health and Nutrition Examination Survey (1988-1994), n=13 095. Multiple regression methods were used to examine the independent associations of BMI, trying to lose weight, or the interaction of BMI-trying to lose weight with reported intakes of energy, nutrients, percentage energy from low-nutrient-density foods (sweeteners, baked and dairy desserts, visible fats and salty snacks), and serum concentrations of vitamins, carotenoids and lipids. RESULTS: BMI was an independent positive predictor (P<0.05) of percentage of energy from fat, saturated fat, but a negative predictor of the ratio of reported energy intake to estimated expenditure for basal needs (EI/BEE), percentage of energy from carbohydrate and alcohol (men only), and serum concentrations of folate, vitamin C, vitamin E and most carotenoids in both men and women. Trying to lose weight was a negative predictor (P<0.05) of EI/BEE, intake of energy, and energy density, but not micronutrient intake. Higher mean serum ascorbate, vitamin E, lutein/zeaxanthin, and other carotenoids (men only) concentrations were associated with trying to lose weight (P<0.05) in both men and women. Few adverse BMI-trying to lose weight interaction effects were noted. CONCLUSIONS: There was little evidence of increased nutritional risk in those reportedly trying to lose weight irrespective of weight status.

Weight-loss attempts and reporting of foods and nutrients, and biomarkers in a national cohort.

OBJECTIVE: This study examined the reported intake of foods and nutrients, and biomarkers of dietary exposure and cardiovascular disease in relation to history of trying to lose weight. METHODS: Dietary, anthropometric and biochemical data were from the third National Health and Nutrition Examination Survey (1988-1994), n=13 092. The history of attempting weight loss variable was created as follows: trying to lose currently and tried in the past 12 months (Y/Y); trying to lose currently, but not tried in the past 12 months (Y/N), not trying currently, but tried in the past 12 months (N/Y); not trying now and not tried in the past 12 months (N/N). Multiple regression methods were used to examine the independent association of history of trying to lose weight with reported intakes of energy, nutrients, percentage energy from low-nutrient-dense foods (sweeteners, baked and dairy desserts, visible fats and salty snacks), and serum concentrations of vitamins, carotenoids and lipids. RESULTS: Men and women in the Y/Y group reported lower energy intake relative to the N/N group (P<0.0000). However, the reported percentage energy from fat and carbohydrate by the Y/Y group did not differ from the N/N group. Percentage of energy from low-nutrient-dense foods was lower in men in the Y/Y group but not women. The relative odds of reporting the estimated average requirement (EAR) of folate, and vitamins A, B(6), B(12), C, E and iron and adequate intake (AI) of calcium were not adversely affected by history of trying to lose weight in men. In women, the odds of meeting the folate and vitamin E EAR were lower in the Y/Y group. Some history of weight loss categories were significant positive predictors of serum vitamin and carotenoid concentrations, or unrelated to cardiovascular disease risk biomarkers. CONCLUSIONS: There was little evidence for increased nutritional risk in those reporting repeat attempts at weight loss.

Rescue of infectious bursal disease virus from mosaic full-length clones composed of serotype I and II cDNA.

Infectious Bursal Disease Virus (IBDV) is the causative agent of one of the most important and wide-spread infectious diseases among commercial chicken flocks. IBDV causes a depletion of B-lymphoid cells in the bursa of Fabricius, inducing immunosuppression, morbidity, or even acute mortality. Because currently used live IBDV vaccines are derivatives from field isolates no serologic discrimination between field isolates and live vaccines can be made. The recently developed reverse genetics techniques for IBDV allows one to generate genetically modified IBDVs which might have altered biological and antigenic properties. Here, we describe the rescue of mosaic serotype I IBDVs, of which the polyprotein encoding region was partly replaced by the corresponding region of a serotype II strain. A mosaic virus, containing the C-terminal part of serotype II VP3 showed only a slightly delayed release of progeny virus compared to unmodified serotype I virus, while maximum viral titers at 25 h post infection were equal. Since serotype specific epitope(s) are present in the C-terminal part of VP3, we were able to discriminate this rescued virus from serotype I and II IBDV strains. These findings make the use of a chimeric VP3 a promising approach to develop an IBDV marker vaccine.

Treatment resistant depression and axis I co-morbidity.

BACKGROUND: Treatment resistant depression (TRD) continues to present a formidable challenge to clinicians, accounts for over half of the annual costs associated with treatment for depression and causes great frustration to patients. Although there have been studies attempting to define TRD, little information is available as to the cause of TRD. One suggestion is that patients with TRD have a greater frequency of co-morbid psychiatric disorders, which explains their resistance to standard antidepressant treatments. The objective of this study was to compare the co-morbidity of Axis I disorders between a sample of TRD patients and a sample of non-TRD patients. METHODS: TRD and non-TRD patients, recruited from two separate antidepressant treatment studies, were assessed for Axis I co-morbidity using the SCID-P for the DSM-III-R. Patients for the two samples were then matched for baseline HAM-D-17 total score and gender. RESULTS: Results reveal that non-TRD patients had a higher rate of both lifetime and current generalized anxiety disorder co-morbidity than did the TRD patients. No other statistically significant differences in Axis I co-morbidity were found. CONCLUSIONS: These findings do not support the idea that current or lifetime Axis I co-morbidity is more common in TRD than non-TRD patients. In fact, the only statistical difference showed non-TRD patients with higher co-morbidity rates.

Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells.

alpha-Galactosylceramide (alphaGalCer) stimulates NKT cells and has antitumor activity in mice. Murine NKT cells may directly kill tumor cells and induce NK cell cytotoxicity, but the mechanisms are not well defined. Newly developed human CD1d/alphaGalCer tetrameric complexes were used to obtain highly purified human alphaGalCer-reactive NKT cell lines (>99%), and the mechanisms of NKT cell cytotoxicity and activation of NK cells were investigated. Human NKT cells were cytotoxic against CD1d(-) neuroblastoma cells only when they were rendered CD1d(+) by transfection and pulsed with alphaGalCer. Four other CD1d(-) tumor cell lines of diverse origin were resistant to NKT cells, whereas Jurkat and U937 leukemia cell lines, which are constitutively CD1d(+), were killed. Killing of the latter was greatly augmented in the presence of alphaGalCer. Upon human CD1d/alphaGalCer recognition, NKT cells induced potent cytotoxicity of NK cells against CD1d(-) neuroblastoma cell lines that were not killed directly by NKT cells. NK cell activation depended upon NKT cell production of IL-2, and was enhanced by secretion of IFN-gamma. These data demonstrate that cytotoxicity of human NKT cells can be CD1d and ligand dependent, and that TCR-stimulated NKT cells produce IL-2 that is required to induce NK cell cytotoxicity. Thus, NKT cells can mediate potent antitumor activity both directly by targeting CD1d and indirectly by activating NK cells.

Consumption of energy-dense, nutrient-poor foods by adult Americans: nutritional and health implications. The third National Health and Nutrition Examination Survey, 1988-1994.

BACKGROUND: Current dietary guidance recommends limiting the intake of energy-dense, nutrient-poor (EDNP) foods, but little is known about recent consumption patterns of these foods. OBJECTIVE: The contribution of EDNP foods to the American diet and the associated nutritional and health implications were examined. DESIGN: Data from the third National Health and Nutrition Examination Survey (n = 15611; age >/=20 y) were used. EDNP categories included visible fats, nutritive sweeteners and sweetened beverages, desserts, and snacks. The potential independent associations of EDNP food intake with intakes of energy, macronutrients, micronutrients, and serum vitamin, lipid, and carotenoid profiles were examined with linear and logistic regression procedures. RESULTS: EDNP foods supplied approximately 27% of energy intake; alcohol provided an additional 4%. The relative odds of consuming foods from all 5 food groups and of meeting the recommended dietary allowance or daily reference intake for protein and several micronutrients decreased with increasing EDNP food intake (P: < 0.0001). Energy intake and percentage of energy from fat were positively related to EDNP intake. Serum concentrations of vitamins A, E, C, and B-12; folate; several carotenoids; and HDL cholesterol were inversely related (P:

A prospective study of diet quality and mortality in women.

CONTEXT: Most studies of diet and health care have focused on the role of single nutrients, foods, or food groups in disease prevention or promotion. Few studies have addressed the health effects of dietary patterns, which include complex mixtures of foods containing multiple nutrients and nonnutrients. OBJECTIVE: To examine the association of mortality with a multifactorial diet quality index. DESIGN AND SETTING: Data from phase 2 (1987-1989) of a prospective cohort study of breast cancer screening, the Breast Cancer Detection Demonstration Project, with a median follow-up of 5.6 years. PARTICIPANTS: A total of 42,254 women (mean age, 61.1 years) who completed the food frequency questionnaire portion of the survey. MAIN OUTCOME MEASURE: All-cause mortality by quartile of Recommended Food Score (RFS; the sum of the number of foods recommended by current dietary guidelines [fruits, vegetables, whole grains, low-fat dairy, and lean meats and poultry] that were reported on the questionnaire to be consumed at least once a week, for a maximum score of 23). RESULTS: There were 2065 deaths due to all causes in the cohort. The RFS was inversely associated with all-cause mortality. Compared with those in the lowest quartile, subjects in the upper quartiles of the RFS had relative risks for all-cause mortality of 0.82 (95% confidence interval [CI], 0.73-0.92) for quartile 2, 0.71 (95% CI, 0.62-0.81) for quartile 3, and 0.69 (95% CI, 0.61-0.78) for quartile 4 adjusted for education, ethnicity, age, body mass index, smoking status, alcohol use, level of physical activity, menopausal hormone use, and history of disease (chi2 for trend = 35.64, P<.001 for trend). CONCLUSIONS: These data suggest that a dietary pattern characterized by consumption of foods recommended in current dietary guidelines is associated with decreased risk of mortality in women.

Studies on the pathogenesis of chicken infectious anaemia virus infection in six-week-old SPF chickens.

The pathogenesis of chicken infectious anaemia virus (CAV) infection was studied in 6-week-old and one-day-old SPF chickens inoculated intramuscularly with graded doses of Cux-1 strain (10(6)-10(2) TCID50/chicken). Viraemia, virus shedding, development of virus neutralizing (VN) antibodies and CAV distribution in the thymus were studied by virus isolation, polymerase chain reaction (PCR), immunocytochemistry (IP) and in situ hybridization until postinfection day (PID) 28. In 6-week-old chickens infected with high doses of CAV, viraemia and VN antibodies could be detected 4 PID and onward without virus shedding or contact transmission to sentinel birds. However, virus shedding and contact transmission were demonstrated in one-day-old infected chickens. In the 6-week-old groups infected with lower doses, VN antibodies developed by PID 14, transient viraemia and virus shedding were detected. The thymus cortex of all 1-day-old inoculated chickens stained with VP3-specific mAb. Cells with positive in situ hybridization signal were fewer and scattered throughout the thymus tissue of the one-day-old inoculated chickens as compared to IP-positive cells. These results suggest that early immune response induced by high doses of CAV in 6-week-old chickens curtails viral replication and prevents virus shedding.

Cbl functions downstream of Src kinases in Fc gamma RI signaling in primary human macrophages.

Cbl is a cytosolic protein that is rapidly tyrosine phosphorylated in response to Fc receptor activation and binds to the adaptor proteins Grb2, CrkL, and Nck. A few reports describe Cbl interactions in primary human hematopoietic cells. We show evidence that Cbl participates in signaling initiated by Fc gammaRI receptor cross-linking in human primary macrophages, and functions downstream of Src family kinases in this pathway. Fc gammaRI stimulation in human macrophages was associated with rapid and transient tyrosine phosphorylation of the Cbl adaptor protein. Immunoprecipitated Cbl was complexed with several tyrosine phosphorylated proteins, the most prominent of which was a 38-kDa band identified as the CrkL adaptor protein. CrkL associated with tyrosine-phosphorylated Cbl and itself became tyrosine phosphorylated after Fc gammaRI cross-linking. SLP-76, a recently cloned Grb2-associated protein, was strongly tyrosine phosphorylated after Fc gammaRI stimulation and was associated with both Cbl and Grb2. Grb2 and Cbl binding to SLP-76 were inducible after Fc gammaRI stimulation of the macrophages. Nck was inducibly bound to Cbl after Fc gammaRI stimulation, whereas Grb2 was constitutively associated with it. Shc was also inducibly tyrosine phosphorylated and bound to Grb2 after Fc gammaRI stimulation of the macrophages. PP1, a specific inhibitor of Src kinases, inhibited the Fc gammaRI-induced respiratory burst, as well as the tyrosine phosphorylation of Cbl and its inducible association with CrkL. These results suggest a fundamental role for the tyrosine phosphorylation of Cbl, CrkL, SLP-76, and Shc and the association of Cbl with CrkL, SLP-76, and Nck in Fc gammaRI signaling in human macrophages. Experiments performed with PP1, the specific Src kinase inhibitor, demonstrate the first evidence that Cbl and the Cbl-Crkl interaction are downstream targets for myeloid Src kinases required for the activation of myeloid NADPH oxidase activity.