Lung eosinophilic inflammation and airway hyperreactivity are enhanced by murine anaphylactic, but not nonanaphylactic, IgG1 antibodies

BACKGROUND: Chronic airway inflammation is a fundamental feature of bronchial asthma, which is characterized by the accumulation and activation of inflammatory cells, such as mast cells and eosinophils, that are tightly regulated by TH2 cytokines and chemokines. Recently, we demonstrated, in a murine model of asthma with immunosuppressed mice reconstituted with antigen-specific IgE or IgG1 antibodies, that IgE, but not IgG1, participates in potentiation of airway inflammation and induction of airway hyperreactivity (AHR). The IgG1 antibody, however, did not elicit passive cutaneous anaphylactic reactions, which was in contrast to IgE. OBJECTIVES: Because 2 types of murine IgG1 have been demonstrated with regard to anaphylactic activity, the present experiments were undertaken to determine the role of anaphylactic and nonanaphylactic IgG1 antibodies in the development of antigen-induced eosinophilia and AHR in this model. METHODS: Dinitrophenyl-conjugated, heat-coagulated hen's egg white was implanted in immunosuppressed mice reconstituted with anaphylactic or nonanaphylactic IgG1. Intratracheal challenge with aggregated dinitrophenyl-ovalbumin was performed on day 14, and lung inflammatory and mechanical parameters were evaluated after 48 hours. RESULTS: Our results demonstrated that reconstitution of immunosuppressed mice with anaphylactic IgG1 antibodies in contrast to nonanaphylactic IgG1 antibodies potentiates their ability to have pulmonary eosinophilic inflammation and AHR. IL-5 and eotaxin levels in bronchoalveolar lavage fluid from anaphylactic IgG1-reconstituted mice were also higher than those in nonanaphylactic IgG1-reconstituted mice. CONCLUSIONS: These results indicate that the anaphylactic property of murine IgG1 molecules is essential for their capacity to enhance lung eosinophilic inflammation and to induce AHR.     

The association of access to medical care with regular source of care and sociodemographic characteristics in patients with HIV and tuberculosis

PURPOSE: To examine satisfaction with access to health care in two populations, one with HIV and one with TB, and examine the effect of having a regular doctor and sociodemographic characteristics. DESIGN: Cross-Sectional survey. PATIENTS: A sample of HIV inpatients hospitalized at seven Los Angeles sites (N = 217) and TB outpatients chosen randomly from the Los Angeles County TB Registry Census (N = 313). ANALYSIS: We performed bivariate and multivariate regression analyses of satisfaction with access to care on gender, race/ethnicity, age, education, income, insurance, and having a regular doctor. MAIN OUTCOME MEASURES: A six-item scale of satisfaction with access to care (range 0-100; Cronbach's alpha 0.87). RESULTS: The mean satisfaction with access score for the HIV sample was significantly lower than the TB sample (53.5 vs. 61.2, p<0.001). The HIV sample multivariate analysis (including all the variables) showed that increasing age (p<0.021 and having a regular doctor (p<0.002) were associated with better access, and that low income (p<0.005) was associated with poor access. In the TB sample analysis, only increasing age was associated with better satisfaction with access to care (p< 0.01). CONCLUSION: HIV patients receiving care in the private sector reported less satisfaction with access to care compared to TB patients receiving care in the public health sector. The traditional factors of socio-economic status and having a regular doctor were associated with satisfaction with access-to-care in the HIV sample but not the TB sample. Our findings suggest that certain characteristics of the TB public health programs may explain these differences and suggests that, perhaps, the existence of a similar public health program for vulnerable low-income populations with HIV would improve their satisfaction with access, as well.     

Human multiple myeloma cells express peroxisome proliferator-activated receptor gamma and undergo apoptosis upon exposure to PPARgamma ligands

Multiple myeloma is essentially an incurable malignancy and it is therefore of great interest to develop new therapeutic approaches. We previously reported that human B cell-lymphomas express the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) and are killed by PPARgamma ligands. Herein, we investigate the therapeutic potential of PPARgamma ligands for multiple myeloma. The human multiple myeloma cell lines ANBL6 and 8226 express PPARgamma mRNA and protein. The PPARgamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone, induced multiple myeloma cell apoptosis as determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, loss of mitochondrial membrane potential, and caspase activation. Importantly, the ability of PPARgamma ligands to kill both multiple myeloma cell lines was not abrogated by Interleukin-6 (IL-6), a multiple myeloma growth survival factor. Finally, the RXR ligand 9-cis retinoic acid (9-cis RA) in combination with PPARgamma ligands greatly enhanced multiple myeloma cell killing. These new findings support that PPARgamma ligands may represent a novel therapy for multiple myeloma.     

Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein

p21 inhibits cyclin-dependent kinase (CDK) activity and proliferating cell nuclear antigen (PCNA)-dependent DNA replication by binding to CDK/cyclin complexes and to PCNA through distinct domains. The human papillomavirus (HPV)-16 E7 oncoprotein (16E7) abrogated a DNA damage-induced cell cycle arrest in vivo, despite high levels of p21. Using cell lysates and purified proteins we show that 16E7 prevented p21 both from inhibiting CDK2/cyclin E activity and PCNA-dependent DNA replication, whereas the nononcogenic HPV-6 E7 had reduced effects. Inactivation of both inhibitory functions of p21 was attained through binding between 16E7 and sequences in the carboxy-terminal end of p21 that overlap with the PCNA-binding site and the second p21 cyclin-binding motif. These data imply that the carboxyl terminus of p21 simultaneously modulates both CDK activity and PCNA-dependent DNA replication and that a single protein, 16E7, can override this modulation to disrupt normal cell cycle control.     

Chronology of halothane-induced antigen expression in halothane-exposed rabbits.

Multiple halothane exposures in rabbits generate modified liver proteins or antigens that appear to incorporate the metabolic intermediate of halothane, trifluoroacetyl halide (TFA), as identified by specific anti-TFA antibody. These halothane-induced antigens are most prevalent throughout the second to fourth days following a single halothane exposure and are in highest concentration after the second and third exposure. In addition, five consecutive halothane exposures at 2-week intervals caused the sustained expression of these halothane-induced antigens throughout the first 4 days following the last exposure. By the seventh day, however, antigen expression began to decline. Although there is great heterogeneity in the molecular weights of the halothane-induced antigens, the predominant proteins appear to be 85k, 58k, 53k, 37k and 24k. These liver proteins could reflect self proteins altered by trifluoroacetylation by halothane metabolites and may be potential immunogens in the initiation of a halothane-induced immune response.     

Effects of the Ebbinghaus figure on grasping are not only due to misjudged size

It is not evident how the small effects of the flankers of the Ebbinghaus figure on peak grip aperture (PGA) should be interpreted. One interpretation is that the flankers influence the estimated size, which in turn influences the grasp. If this interpretation is correct, then only the size-dependent aspects of the grasping movement should depend on the spatial positions of the flankers. An alternative interpretation is that the effect on grip aperture is caused by a change in judgement of the required precision, in which case various aspects of the grasping movement could be influenced by the size and position of the flankers. We presented subjects with a display consisting of a central disk surrounded by four large or small flankers. The array of circular flankers could be rotated by 45°. There were two tasks: to reproduce the perceived size of the central disk, and to grasp the central disk. As in other studies, the reproduced size and the PGA were both influenced by the size of the flankers. The effect on reproduced size settings was independent of the flankers spatial position. Nevertheless, the flankers position did influence the final grip aperture and the grip orientation at PGA and at movement offset. Because the flankers changed more than only the PGA, we conclude that the effect of the flankers on prehension cannot only be because of misjudgement of the size of the central disk.     

Factors affecting the determination of threshold doses for allergenic foods: how much is too much?

BACKGROUND: Ingestion of small amounts of an offending food can elicit adverse reactions in individuals with IgE-mediated food allergies. The threshold dose for provocation of such reactions is often considered to be zero. However, because of various practical limitations in food production and processing, foods may occasionally contain trace residues of the offending food. Are these very low, residual quantities hazardous to allergic consumers? How much of the offending food is too much? Very little quantitative information exists to allow any risk assessments to be conducted by the food industry. OBJECTIVE: We sought to determine whether the quality and quantity of existing clinical data on threshold doses for commonly allergenic foods were sufficient to allow consensus to be reached on establishment of threshold doses for specific foods. METHODS: In September 1999, 12 clinical allergists and other interested parties were invited to participate in a roundtable conference to share existing data on threshold doses and to discuss clinical approaches that would allow the acquisition of that information. RESULTS: Considerable data were identified in clinical files relating to the threshold doses for peanut, cows' milk, and egg; limited data were available for other foods, such as fish and mustard. CONCLUSIONS: Because these data were often obtained by means of different protocols, the estimation of a threshold dose was very difficult. Development of a standardized protocol for clinical experiments to allow determination of the threshold dose is needed.     

A concept-based retrieval system for thoracic radiology

Current digital information systems in radiology are insufficient to accommodate the retrieval needs of academicians. Significant efforts are required in retrieving clinical cases for teaching and research. We describe a prototype system that supports intelligent case retrieval based on a combined specification of patient demographics, radiologic findings, and pathologic diagnoses. The documents for these cases can be distributed among multiple heterogeneous data bases. The system features automatic indexing of radiology and pathology reports, a comprehensive lexicon for thoracic radiology, an interface to a hospital information system, radiology information system, and picture archiving and communication systems, and a graphical user interface for query formulation and results visualization. The prototype system was developed within the domain of thoracic radiology involving patients with lung cancer.     

Predictors of low CD4 count in resource-limited settings: based on an antiretroviral-naive heterosexual thai population

A barrier to the appropriate provision of antiretroviral therapy to treat immunosuppressed HIV-infected persons in resource-poor countries is identifying who requires treatment. The World Health Organization (WHO) has suggested using a clinical algorithm combined with a total lymphocyte count (TLC) < 1200 cells/mm as a surrogate for a CD4 count less than 200 cells/mm when it is not possible to measure the CD4 count. We evaluated various TLC levels, anemia, and body mass index and compared our data with the WHO criteria to develop a more sensitive algorithm to predict CD4 counts of < 200 cells/mm and < 350 cells/mm in 839 men and women from Thailand infected with HIV-1 subtype E (CRF01_AE). The December 2003 WHO guidelines had a sensitivity of 34.1% in men and 31.8% in women to detect persons with a CD4 count < 200 cells/mm in this HIV-infected population from Thailand. The use of a TLC < 1500 cells/mm or TLC < 2000 cells/mm combined with anemia or WHO stage II infection doubled the sensitivity to detect persons with a CD4 count < 200 (63.0% in men, 68.2% in women) with less than a 6% decrease in specificity.     

Sclerosing mucoepidermoid carcinoma of the parotid gland

Although mucoepidermoid carcinoma is the most common primary malignancy of the salivary glands, the sclerosing morphologic variant of this tumor is extremely rare, with only 6 reported cases. As its name suggests, sclerosing mucoepidermoid carcinoma is characterized by an intense central sclerosis that occupies the entirety of an otherwise typical tumor, frequently with an inflammatory infiltrate of plasma cells, eosinophils, and/or lymphocytes at its peripheral regions. The sclerosis associated with these tumors may obscure their typical morphologic features and result in diagnostic difficulties. Tumor infarction and extravasation of mucin eventuating in reactive fibrosis are 2 mechanisms of formation that have been suggested as underlying this morphologic variant. We describe herein another case of sclerosing mucoepidermoid carcinoma that was diagnosed in a 44-year-old woman and review the relevant literature. Morphologic evidence in support of the mucin extravasation hypothesis was identified, as small pools of mucin were present throughout the tumor. However, there was no concentration of the mucin pools near the areas with the most viable tumor cells, which would have provided evidence for a temporal sequence that eventuates in lack of mucin in the most sclerotic regions.