Predictors of cardiopulmonary fitness in cancer-affected and -unaffected women with a pathogenic germline variant in the genes BRCA1/2 (LIBRE-1).

Physical activity (PA) helps prevention and aftercare of sporadic breast cancer (BC), cardiopulmonary fitness (CPF) being an age-independent predictor of tumor-specific mortality. Therefore, we wanted to identify predictors of CPF (represented by peak oxygen uptake: VO2peak) in BRCA1/2 mutation carriers whose risk of developing BC is high. We used cross-sectional data from 68 BRCA1/2 germline mutation carrying women participating in the randomized, prospective, controlled clinical study LIBRE-1. Assessments included cardiopulmonary exercise testing, medical and lifestyle history plus socioeconomic status. Additionally, the participants completed a psychological questionnaire regarding their attitude, subjective norms, perceived behavior control and intention towards PA. A multivariate logistic regression model was used to identify predictors for participants reaching their age- and sex-adjusted VO2peak reference values. 22 participants (median age: 40 years, interquartile range (IQR) 33-46) were cancer-unaffected and 46 cancer-affected (median age: 44 years, IQR 35-50). The strongest predictor for reaching the reference VO2peak value was attitude towards PA (Odds Ratio 3.0; 95% Confidence Interval 1.3-8.4; p = 0.021). None of the other predictors showed a significant association. A positive attitude towards PA seems to be associated with VO2peak, which should be considered in developing therapeutic and preventive strategies.Trial registrations: NCT02087592; DRKS00005736.

Expression and function of Fas (APO-1/CD95) in patient myeloma cells and myeloma cell lines.

Cross-linkage of the Fas antigen induces programmed cell death in many normal and malignant lymphoid cells by a process known as apoptosis. In this study, we examined the sensitivity of myeloma cell lines and patient plasma cells to a cytolytic anti-Fas monoclonal antibody (MoAb). Eight of 10 myeloma cell lines were induced to undergo programmed cell death by anti-Fas MoAb as determined by DNA fragmentation and morphologic changes. Of the two myeloma cell lines that were resistant to anti-Fas treatment, one did not express the Fas antigen. Only the U266 cell line expressed Fas, but was not killed by the anti0Fas MoAb. To extend these studies, we have examined the expression and function of Fas in freshly isolated CD38hiCD45neg-int plasma cells from patients with multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and primary amyloidosis (AL). By three-color flow cytometry, we found Fas expression in CD38hiCD45neg-int plasma cells from all patient groups to be variable, as Fas was expressed in 15 of 28 MM, 3 of 6 MGUS, and 2 of 7 AL patients. In morphologic studies of apoptosis, Fas-positive myeloma cells in patient bone marrow mononuclear cell (MNC) cultures appeared to be resistant to anti-Fas-mediated apoptosis. By contrast, purified myeloma cells from the same patient were sensitive to anti-Fas treatment, suggesting the presence of a protective factor(s) in unseparated MNC cultures that may inhibit Fas-induced apoptosis of plasma cells. Of interest, serum from normal individuals and myeloma patients also protected myeloma cell lines from undergoing Fas-mediated apoptosis. These studies show that Fas expression in myeloma cell lines and CD38hiCD45neg-int patient plasma cells is variable and may reflect a variance in the maturation status of the various plasma cell populations. Moreover, Fas-mediated killing of patient cells and myeloma cell lines was also variable, which may be influenced, in part, by the presence of a soluble protective factor.

Bronchoalveolar lavage cell populations in the diagnosis of sarcoidosis.

STUDY DESIGN: Between February 1, 1984, and February 1, 1989, fiberoptic bronchoscopy was performed on 2,692 patients, 592 of whom had bronchoalveolar lavage (BAL). One hundred twenty-eight patients with 16 percent or more lymphocytes in BAL fluid (BALF) were selected for further study. The group included 27 patients with sarcoidosis, 28 with nonsarcoidosis interstitial lung disease (ILD), 22 with lung infection (organism isolated), 31 with inflammation (presumed infection, no organism isolated), 14 with neoplasm, and 6 with bronchial hyperreactivity. METHODS: The percentages of lymphocytes, B lymphocytes, and T lymphocytes, the CD4/CD8 ratio and the percentages of neutrophils and eosinophils were analyzed individually and in combination for discrimination between the sarcoidosis and nonsarcoidosis patients and compared with the diagnostic accuracy of multiple noncaseating granuloma (MNG) on a simultaneous transbronchial biopsy (Tbbx). RESULTS: Neither the percentages of lymphocytes, T lymphocytes, or B lymphocytes discriminated sarcoidosis from nonsarcoidosis patients. Sarcoidosis patients had higher CD4/CD8 ratios, fewer neutrophils, and 1 percent or less eosinophils in the BAL cell populations. An analysis of CD4/CD8 ratios, and percentages of neutrophils and eosinophils individually revealed that a CD4/CD8 ratio of 4:1 or greater had a positive predictive value of 94 percent in distinguishing sarcoidosis from other ILD but a sensitivity of only 59 percent. The positive predictive value of CD4/CD8 ratio of 4:1 or greater fell to 50 percent in separating sarcoidosis from all other diseases. A CD4/CD8 ratio of less than 1:1 has a 100 percent negative predictive value to exclude the diagnosis of sarcoidosis. Finding 1 percent or less neutrophils in BAL had an 80 percent positive predictive value in distinguishing sarcoidosis from nonsarcoidosis ILD and 51 percent for distinguishing sarcoidosis from all other disease groups. The CD4/CD8 ratio and the percentages of neutrophils and eosinophils also were combined and analyzed for the diagnosis of sarcoidosis. CONCLUSIONS: Results showed a BALF with a CD4/CD8 ratio of 2:1 or greater, 1 percent or less neutrophils, and 1 percent or less eosinophils has essentially the same specificity and positive predictive value as MNG on Tbbx in distinguishing sarcoidosis from nonsarcoidosis disease. The combination of finding MNG in a Tbbx specimen plus a BALF CD4/CD8 ratio of 4:1 or greater had a 100 percent positive predictive value in separating sarcoidosis from other ILD and an 81 percent value in separating sarcoidosis from all other disease. Finding MNG in a Tbbx specimen plus a BALF with a CD4/CD8 ratio of 2:1 or greater, 1 percent or less neutrophils, and 1 percent or less eosinophils had a 93 percent positive predictive value in distinguishing sarcoidosis from both nonsarcoidosis ILD and all other diseases.

Use of methotrexate in the treatment of steroid-dependent adolescent asthmatics.

Five children 10 to 16 years of age with steroid-dependent asthma were treated with methotrexate. All were able to reduce their doses of prednisone and all had improvement in their clinical status. No significant side effects were noted in patients treated 1 to 3 years. This open study suggests that methotrexate should be considered in the treatment of older children with severe asthma and morbidity from their steroid therapy.

Long-term methotrexate treatment in corticosteroid-dependent asthma.

STUDY OBJECTIVE: To study the long-term efficacy and toxicity of low-dose methotrexate as corticosteroid-sparing adjunctive therapy in patients with corticosteroid-dependent bronchial asthma. DESIGN: A prospectively evaluated case series. PATIENTS: We studied 31 cushingoid asthmatics who needed daily prednisone and were found to be unable to reduce their prednisone dosage. These patients had used maximal daily doses of bronchodilator and inhaled corticosteroid and, on average, had used prednisone, 26.8 mg/d, for 4.7 years (range, 1 to 11 years). Of these 31 patients, 25 completed 18 to 28 months of methotrexate therapy. INTERVENTION: Patients were treated for at least 18 months with low-dose methotrexate (range, 15 to 50 mg/wk). RESULTS: The mean prednisone dose was reduced from 26.9 mg/d to 6.3 mg/d (P = 0.0001) in the 25 patients treated with long-term methotrexate: Fifteen patients discontinued the regular use of prednisone, 9 patients reduced prednisone use by more than 50%, and 1 patient failed to respond. The forced expiratory volume in 1 second (FEV1) improved from 1.7 L/s to 1.9 L/s (P = 0.0513), and subjective symptom scores for breathing ability, cough, wheeze, and frequency of nocturnal awakenings all improved. Adverse drug reactions were noted in 15 patients. These reactions were mild and did not lead to discontinuation of drug therapy. CONCLUSION: Methotrexate is effective and safe when used as a long-term, corticosteroid sparing agent in patients with severe bronchial asthma.

Cytotoxic cells induced after Chlamydia psittaci infection in mice.

The ability of spleen cells from Chlamydia psittaci-infected mice to lyse C. psittaci-infected and uninfected target cell monolayers was studied. The cytotoxicity assay used was a terminal label method in which the number of adherent target cells surviving the interaction with effector cells was determined by measuring the uptake of [3H]uridine by such cells. It was observed that in the first few days postinfection (3 to 5), spleens contained cells that lysed infected and uninfected targets with equal efficiency. Subsequently, infected targets were killed primarily. The activity of effector spleen cells for infected targets continued, although at a reduced level, beyond 21 days postinfection. Intact effector cells were required since a disruption by sonication resulted in a loss of cytotoxicity. The enhanced killing observed with infected targets was also observed when target cells were sensitized with heat- or UV-inactivated C. psittaci. This study suggests that the induction of cytotoxic cells after C. psittaci infection may contribute to the ability of the host to control multiplication of the microorganism.

Modulation of the host immune response as a result of Chlamydia psittaci infection.

After intraperitoneal injection of mice with infectious, inactivated, or envelope preparations of the elementary body of Chlamydia psittaci, lymphocyte transformation of spleen cells to the mitogens concanavalin A, phytohemagglutinin, and lipopolysaccharide was significantly reduced 1 and 2 weeks postinjection. Lymphocyte response returned to the control values by 4 weeks. Similarly, transformation of cells by chlamydial antigen was not detected until 4 weeks postinjection. Injection of the noninfectious intracellular reticulate body, in contrast, had little effect on transformation of cells to concanavalin A. When control spleen cells were incubated with infectious or inactivated elementary bodies in vitro, response to all three mitogens was also reduced. The sooner the organisms were added after the addition of mitogen, the greater the reduction in transformation. Incubation with elementary body envelopes and reticulate bodies had no effect on lymphocyte transformation of the spleen cells to concanavalin A. The relationship between the observed ability to reduce the response in the in vitro assay of lymphocyte transformation and the actual in vivo establishment of infection is discussed.

Mutagenicity of filtrates from respirable coal fly ash.

Incubation of histidine-requiring auxotrophs of the bacterium Salmonella typhimurium with cyclohexane-, saline-, and serum-soluble surface components of respirable fly ash particles produced an increased number of revertants in two frameshift tester strains. The results are consistent with the hypothesis that both organic and inorganic mutagens are present in coal fly ash.

Additional rabbit IgA allotypes, f69, f70, g76,g77: control by the C alphaf and C alphag loci.

Genetic and immunochemical studies have led to the identification of four additional rabbit IgA allotypes controlled by the Calphaf and Calphag loci. The folowing linkage combinations of the VHa and the 'new' alleles were observed among the populations of rabbits studied: a1f70g76, a1f69g77, and a2f69g77. Cross-reactions among g74, g76, and g77 molecules with various anti-g anti-allotype antisera indicate that the IgA-g allotypic specificities are comprised of multiple antigenic determinants. These studies provide a basis for further understanding of the evolution and gnetic control of the immunoglobulin heavy chain chromosomal region.

Quantitative separation of nucleotides on mercurated dextran.

Dextran gels of varying porosites (Sephadex G series) were chemically modified so as to contain covalently bound monofunctional mercury. Mercurated Sephadex of the porosity G-25 was then used to fractionate mixtures of mono- and dinucleotides into the constituent components. Separation is based on the affinity of the nitrogen binding sites of the purine and pyrimidine derivatives for organomercurial Hg+. Thus, a mixture composed of the four mononucleotides Cyd-5'-P, Ado-3'-P, Guo-2'(3')-P, dThd-5'-P and of the four dinucleotides Cyd-P-Cyd, Ado-P-Ado, Guo-P-Urd, and Urd-P-Urd could be separated into eight well-resolved fractions by using a combination Tris-bicarbonate/carbonate buffer system of increasing pH as an eluent. Complete separation was also achieved when a mixture of Ado 3:5'-P, Ado 5'-P, Ado-5'-PP, and Ado-5'-PPP was fractionated on mercurated Sephadex G-25. Again, Tris-bicarbonate/carbonate buffer served as an eluent. Lastly, fractionation can also be performed at a constant pH by offering other suitable ligands, for instance Cl-, that will compete with nucleotides for monofunctional Hg+. The fractionation behavior of mercurated Sephadex G-25 can be fully understood on the basis of the complexing properties of monofunctional Hg+. This has been shown by calculating the net retention volume ratios of several nucleotides with the help of the known interaction parameters of corresponding nucleosides with CH3 HgOH and by comparing the predicted ratios with the experimentally measured ones. Finally, the acid-base properties of mercurated Sephadex G-25 as well as its affinity for chloride and iodide ions have been determined. The data agree quite well with those known for CH3 HgOH.