The Death Receptor 3-TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints that is associated with cartilage and bone destruction. Death Receptor 3 (DR3), a tumor necrosis factor (TNF) receptor superfamily member, has recently been associated with the pathogenesis of RA. We demonstrate that absence of DR3 confers resistance to the development of adverse bone pathology in experimental antigen-induced arthritis (AIA). DR3^ko mice exhibited a reduction in all histopathological hallmarks of AIA but, in particular, failed to develop subchondral bone erosions and were completely protected from this characteristic of AIA. In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion. Analysis of osteoclast number within AIA joint revealed a reduction in areas susceptible to bone erosion in DR3^ko mice, whereas in vitro osteoclastogenesis assays showed that TL1A could directly promote osteoclastogenesis in mouse and man. Treatment with antagonistic anti-TL1A mAb protected animals in a systemic model of RA disease collagen-induced arthritis. We therefore conclude that the DR3–TL1A pathway regulates joint destruction in two murine models of arthritis and represents a potential novel target for therapeutic intervention in inflammatory joint disease.     

Activation and inhibition of adenylyl cyclase isoforms by forskolin analogs

Adenylyl cyclase (AC) isoforms 1 to 9 are differentially expressed in tissues and constitute an interesting drug target. ACs 1 to 8 are activated by the diterpene, forskolin (FS). It is unfortunate that there is a paucity of AC isoform-selective activators. To develop such compounds, an understanding of the structure/activity relationships of diterpenes is necessary. Therefore, we examined the effects of FS and nine FS analogs on ACs 1, 2, and 5 expressed in Spodoptera frugiperda insect cells. Diterpenes showed the highest potencies at AC1 and the lowest potencies at AC2. We identified full agonists, partial agonists, antagonists, and inverse agonists, i.e., diterpenes that reduced basal AC activity. Each AC isoform exhibited a distinct pharmacological profile. AC2 showed the highest basal activity of all AC isoforms and highest sensitivity to inverse agonistic effects of 1-deoxy-forskolin, 7-deacetyl-1,9-dideoxy-forskolin, and, particularly, BODIPY-forskolin. In contrast, BODIPY-forskolin acted as partial agonist at the other ACs. 1-Deoxy-forskolin analogs were devoid of agonistic activity at ACs but antagonized the effects of FS in a mixed competitive/noncompetitive manner. At purified catalytic AC subunits, BODIPY-forskolin acted as weak partial agonist/strong partial antagonist. Molecular modeling revealed that the BODIPY group rotates promiscuously outside of the FS-binding site. Collectively, ACs are not uniformly activated and inhibited by FS and FS analogs, demonstrating the feasibility to design isoform-selective FS analogs. The two- and multiple-state models, originally developed to conceptualize ligand effects at G-protein-coupled receptors, can be applied to ACs to explain certain experimental data.     

Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: a case series analysis

BACKGROUND: This case series summarizes our observations of hemolytic reactions after the administration of large amounts of intravenous immune (gamma) globulin (IVIG). STUDY DESIGN AND METHODS: Cases of hemolysis were identified by a decrease in hemoglobin not otherwise explained following IVIG administration. RESULTS: Sixteen cases were identified over a 2 1/2-year period at the Ottawa Hospital of approximately 1000 patients receiving IVIG (1.6%). Characteristics of these patients include a large dose of IVIG, female sex, non-O blood group, and underlying inflammatory state. CONCLUSIONS: Significant hemolysis may occur after the administration of large doses of IVIG. A two-step mechanism of hemolysis is proposed, sensitization by ABO isohemagglutinins followed by phagocytosis by activated macrophages. A simple protocol to facilitate the early detection of such cases is presented.     

Comparison of antimicrobial resistance profiles among extended-spectrum-beta-lactamase-producing and acquired AmpC beta-lactamase-producing Escherichia coli isolates from Canadian intensive care units

Resistance profiles were compared among 18 extended-spectrum-beta-lactamase-producing (ESBL) and 27 acquired AmpC beta-lactamase-producing Escherichia coli isolates collected from Canadian intensive care units from 2005 to 2006. ESBL-producing E. coli isolates were more likely to be gentamicin resistant (P < 0.03), fluoroquinolone resistant (P < 0.0001), and multidrug resistant (P < 0.0001) than AmpC-producing E. coli isolates.     

Over-the-counter cough and cold medication use in young children

During a 2-year period from 2004 and 2005, emergency departments treated over 1,500 children under the age of 2 years for adverse events related to over-the-counter (OTC) cough and cold medication use; these incidents include 3 infant deaths. The risk of overdose, incorrect dosing and adverse events is increased in young children due to the greater number of colds they acquire each year. Lack of evidence to support the use of OTC medications in young children is well documented in the literature; however, people continue to use OTC medications with young children. The common cold is generally a mild, self-limited illness that usually improves with time. Recommended care and treatment for the common cold includes symptomatic treatment. This article presents and reviews the available evidence regarding the use of OTC cough and cold medications for pediatric healthcare providers. This review of the evidence will be helpful for healthcare providers to minimize risks to young children who intentionally or unintentionally ingest these medications and to educate child caregivers regarding proper use of OTC cough and cold medications with children.     

Could pets be of help in achieving health literacy? A media analysis demonstration study

This paper asks whether, when seeking to reach the public, interest in the health of pets merits consideration. Our data set consisted of 128 items from Canadian media coverage, 1996-2006, that dealt with bovine spongiform encephalopathy (BSE) as well as with cats, dogs or both. Three main messages regarding pet health and human health were identified: 'do not worry', 'do worry' and 'be cautious'. A minority of articles did not convey a pet health message or a human health message (6%), and contradictory messages regarding human and animal health frequently occurred (32%). While we did not assess how members of the public actually received or interpreted these messages, media coverage dealing with pets does appear to have the potential to influence people. Media reports of British cats being harmed by BSE, in fact, may have influenced public views worldwide. Thus, professionals should give careful consideration to pets when conveying health information. Nevertheless, we do not suggest pet health information substitute for human health information. Rather, interest in pets may provide an opportunity to complement and to reinforce communication about human health.     

Chia seed does not promote weight loss or alter disease risk factors in overweight adults

The objective of this study was to assess the effectiveness of chia seed (Salvia hispanica L) in promoting weight loss and altering disease risk factors in overweight adults. The hypothesis was that the high dietary fiber and α-linolenic (ALA) contents of chia seed would induce a small but significant decrease in body weight and fat and improve disease risk factors. Subjects were randomized to chia seed (CS) and placebo (P) groups, and under single-blinded procedures, ingested 25 g CS or P supplements mixed in 0.25 L water twice daily before the first and last meal for 12 weeks. Ninety nondiseased, overweight/obese men and women between the ages of 20 and 70 years were recruited into the study, with 76 subjects (n = 39 CS, n = 37 P) completing all phases of the study. Pre- and poststudy measures included body mass and composition (dual energy x-ray absorptiometry), inflammation markers from fasting blood samples (C-reactive protein, interleukin 6, monocyte chemoattractant protein 1, and tumor necrosis factor α), oxidative stress markers (trolox equivalent antioxidant capacity and plasma nitrite), blood pressure, and a serum lipid profile. Plasma ALA increased 24.4% compared to a 2.8% decrease in CS and P, respectively (interaction effect, P = .012). No group differences were measured for changes in plasma eicosapentaenoic acid and docosahexaenoic acid (interaction effects, P = .420 and .980, respectively). Pre-to-post measures of body composition, inflammation, oxidative stress, blood pressure, and lipoproteins did not differ between CS and P for both sexes. In conclusion, ingestion of 50 g/d CS vs P for 12 weeks by overweight/obese men and women had no influence on body mass or composition, or various disease risk factor measures.     

Multiple indicator hidden Markov model with an application to medical utilization data

Monthly counts of medical visits across several years for persons identified to have alcoholism problems are modeled using two-state hidden Markov models (HMM) in order to describe the effect of alcoholism treatment on the likelihood of persons to be in a 'healthy' or 'unhealthy' state. The medical visits can be classified into different types leading to multivariate counts of medical visits each month. A multiple indicator HMM is introduced, which simultaneously fits the multivariate Poisson counts by assuming a shared hidden state underlying all of them. The multiple indicator HMM borrows information across different types of medical encounters. A univariate HMM based on the total count across types of medical visits each month is also considered. Comparisons between the multiple indicator HMM and the total count HMM are made, as well as comparisons with more traditional longitudinal models that directly model the counts. A Bayesian framework is used for the estimation of the HMM and implementation is in Winbugs.