Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-beta in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice

Prostaglandin E(2) (PGE(2)) inhibits fibroblast proliferation and collagen production. Its synthesis by fibroblasts is induced by profibrotic mediators including transforming growth factor (TGF)-beta(1). However, in patients with pulmonary fibrosis, PGE(2) levels are decreased. In this study we examined the effect of TGF-beta(1) on PGE(2) synthesis, proliferation, collagen production, and cyclooxygenase (COX) mRNA levels in fibroblasts derived from fibrotic and nonfibrotic human lung. In addition, we examined the effect of bleomycin-induced pulmonary fibrosis in COX-2-deficient mice. We demonstrate that basal and TGF-beta(1)-induced PGE(2) synthesis is limited in fibroblasts from fibrotic lung. Functionally, this correlates with a loss of the anti-proliferative response to TGF-beta(1). This failure to induce PGE(2) synthesis is because of an inability to up-regulate COX-2 mRNA levels in these fibroblasts. Furthermore, mice deficient in COX-2 exhibit an enhanced response to bleomycin. We conclude that a decreased capacity to up-regulate COX-2 expression and COX-2-derived PGE(2) synthesis in the presence of increasing levels of profibrotic mediators such as TGF-beta(1) may lead to unopposed fibroblast proliferation and collagen synthesis and contribute to the pathogenesis of pulmonary fibrosis.     

The mutational specificity of l-nitroso-6-nitropyrene in the lacI gene of Escherichia coli strains deficient in nucleotide excision repair

We have examined the mutational specificity of 1-nitroso-6-nitropyrene(1,6-NONP), an activated metabolite of the carcinogen 1,6-dinitropyrene,in the lacI gene of Escherichia coli strains which are deficientin nucleotide excision repair (strain NR6113,     

Reactivity and assay restriction profiles of monoclonal and polyclonal antibodies to acid phosphatases: a preliminary study

The development of secure diagnostic immunoassays requires, among others, rigorous characterisation of potential antibody reagents. The reactivity profiles of seven antibodies (six monoclonal [MAb] and one polyclonal [PAb]) with putative specificity for tartrate-resistant acid phosphatase (TRAP) and/or osteoclasts were evaluated in enzyme-linked immunosorbent assay (ELISA) and/or immunocytochemistry. MAbs 2H1, 4E6 and 5Cl demonstrated assay restriction: exhibiting reactivity only in ELISA. The remaining three MAbs (G211D, G312G and V35B) and the PAb 8023 recognised recombinant TRAP (rTRAP) in ELISA and native acid phosphatases in selected tissues and cell lines. The latter were cytochemically assessed for both tartrate-sensitive acid phosphatase (TSAP) and TRAP. V35B showed reactivity against the monocytic leukaemia cell line U937 and guinea pig kidney tissue (both TSAP+ and TRAP+) and ECV304 (TSAP+) cells. Interestingly, the reactivity of MAb G211D co-localised with TRAP activity in the membrane of osteoclasts but also detected cytoplasmic components in U937 cells and human embryonic lung fibroblasts (TRAP+ and TRAP+). G211D exhibited immunoreactivity against placental trophoblasts (positive for total AP). Intriguingly, MAbs 2H1, 4E6, 5Cl and PAb 8023 cross-reacted with potato acid phosphatase in ELISA, suggesting reactivity to conformationally similar epitopes. Thus, some of these reagents could be used in the development of standardised diagnostic immunoassays or as drug-targeting agents for conditions in which the pathological process involves bone resorption, the MAbs G211D, 2H1, 4E6, 5Cl and PAb 8023 being useful in ELISA but not immunocytochemical detection of TRAP.     

Human aggression and enumerative measures of immunity

OBJECTIVE: A pattern of clinical, behavioral, and experimental findings suggests that individual differences in aggressive behavior may be related to immunologic processes. We evaluated two conflicting models of the relationship: 1) A positive association stems from an adaptive mechanism protecting aggressive individuals from increased exposure to immune stimuli and 2) a negative association is due to potential immunosuppressive effects of high testosterone levels. METHODS: We investigated the models using enumerative measures of cellular and humoral immunity in a sample of 4415 men aged 30 to 48 years who were interviewed and underwent a medical examination. RESULTS: Analysis revealed positive (and curvilinear) associations between aggressive behavior and enumerative measures of helper/inducer and suppressor/cytolytic T lymphocytes and B lymphocytes. The aggression-immunity relationship was independent of testosterone level, age, current health status, and negative health behaviors and was most pronounced for helper/inducer T cells. There was no evidence of a negative association between testosterone and any immune measure. CONCLUSIONS: In a large sample of men, individual differences in aggressive behavior were positively associated with enumerative measures of cellular immunity.     

Comparison of a new enzyme-linked immunosorbent assay method with counterimmunoelectrophoresis for detection of teichoic acid antibodies in sera from patients with Staphylococcus aureus infections

Ribitol-teichoic acid antibodies were measured by a new enzyme-linked immunosorbent assay (ELISA) and by counterimmunoelectrophoresis in serum samples from 47 patients with serious Staphylococcus aureus infections, 63 infected patients, and 177 healthy controls. The same antigen was used for both tests. The group of patients with S. aureus endocarditis (6 patients) had significantly higher ELISA readings than the patients with other deep-seated infections (26 patients) or with an uncomplicated S. aureus bacteremia (15 patients). The patients with other serious gram-positive (40 patients) or gram-negative (23 patients) infections did not differ from the healthy control group. There were only three (7.5%) low-level cross-reactions among the infections caused by gram-positive organisms other than S. aureus. Of 46 initially ribitol-teichoic acid antibody-negative patients followed up for 2 weeks or more, only those developing a serious S. aureus infection showed a significant rise of the ELISA reading. There was a good correlation between ELISA and counterimmunoelectrophoresis. Both tests could be useful in the diagnosis and the management of complicated S. aureus infections. The ELISA method is, however, more sensitive and usually reflects the antibody rise after an infection earlier than does counterimmunoelectrophoresis.     

Further assessment of the effects of occupational radiation exposure in the United Kingdom Atomic Energy Authority mortality study

The United Kingdom Atomic Energy Authority mortality study was designed to investigate the relation between exposure to ionising radiation and mortality among the authority's employees. The present paper describes some of the problems encountered in assessing occupational exposure to low dose radiation and examines whether the study's conclusions about the relation between exposure and mortality could be affected by the methods used. The study covered the years 1946 to 1979 during which time the frequency with which personal film dosimeters were issued changed from weekly to monthly, and the threshold level below which measurements were not made decreased 20-fold. Exposure from "below threshold" readings made an important contribution to total exposure in the early years. Estimates, based on the remeasurement of a sample of old films, indicated that the average whole body exposure before 1961 may have been about double that which was measured. Furthermore, although records were kept of when dosimeters were lost or damaged, the associated exposures were unknown and could only be estimated. Workers whose dosimeter readings were missing for more than 5% of the time during which they were monitored had higher all cause mortality (p = 0.04) and higher mortality from accidents and violence (p = 0.05) than other radiation workers. The results of analyses of mortality in relation to whole body exposure were compared when the exposures included estimates of the below threshold and missing exposures and when these exposures were assumed to be zero. Some of the findings differed, but none changed sufficiently to alter the general conclusions. Although the trend in mortality from all cancers changed from one in which the increase with exposure was far from statistically significant (p = 0.3) when the below threshold and missing values were assumed to be zero to one that approached significance (p = 0.06) after they were estimated, calculations of the annual excess deaths from cancer per unit dose resulted in broadly similar estimates. Studies of workers exposed to ionising radiation usually focus on mortality in relation to whole body exposure. In the present paper its relation to neutron and surface exposure is also examined. Workers with measured neutron exposures had significantly lower all cause mortality than other workers with a radiation record (p = 0.03). Surface exposure was significantly related to mortality from all cancers (p = 0.02) and prostatic cancer (p less than 0.001). Some data on cancer registration are presented but these cannot be readily interpreted because cancer registration details were available only for ex-employees who may not be typical of the workforce as a whole.     

The human pineal gland: a review of the "third eye" and the effect of light

The human pineal gland is an extremely active neuroendocrine transducer. Environmental light acts through the retina and entrains the pineal gland's circadian rhythms by way of the hypothalamus and sympathetic nervous system. Light depresses pinealocyte activity. It is possible to do without the pineal, but this tiny gland is considered to be the "regulator of regulators" and important in general homeostasis. A direct retino-hypothalamic pathway is probably involved; and a system of synchronizing potentially independent oscillators is postulated.     

Components of the Gut Microbiome That Influence Bone Tissue-Level Strength

Modifications to the constituents of the gut microbiome influence bone density and tissue-level strength, but the specific microbial components that influence tissue-level strength in bone are not known. Here, we selectively modify constituents of the gut microbiota using narrow-spectrum antibiotics to identify components of the microbiome associated with changes in bone mechanical and material properties. Male C57BL/6J mice (4 weeks) were divided into seven groups (n = 7–10/group) and had taxa within the gut microbiome removed through dosing with: (i) ampicillin; (ii) neomycin; (iii) vancomycin; (iv) metronidazole; (v) a cocktail of all four antibiotics together (with zero-calorie sweetener to ensure intake); (vi) zero-calorie sweetener only; or (vii) no additive (untreated) for 12 weeks. Individual antibiotics remove only some taxa from the gut, while the cocktail of all four removes almost all microbes. After accounting for differences in geometry, whole bone strength was reduced in animals with gut microbiome modified by neomycin (−28%, p = 0.002) and was increased in the group in which the gut microbiome was altered by sweetener alone (+39%, p < 0.001). Analysis of the fecal microbiota detected seven lower-ranked taxa differentially abundant in animals with impaired tissue-level strength and 14 differentially abundant taxa associated with increased tissue-level strength. Histological and serum markers of bone turnover and trabecular bone volume per tissue volume (BV/TV) did not differ among groups. These findings demonstrate that modifications to the taxonomic components of the gut microbiome have the potential to decrease or increase tissue-level strength of bone independent of bone quantity and without noticeable changes in bone turnover. © 2021 American Society for Bone and Mineral Research (ASBMR).