Treatment of idiopathic inflammatory myositis associated interstitial lung disease: A systematic review and meta-analysis

Objective

Interstitial lung disease (ILD) is the most severe complication of idiopathic inflammatory myositis (IIM), resulting in significant increase in morbidity and mortality and for which the best treatment remains controversial. We conducted a meta-analysis to evaluate the efficacy of therapies used for the management of IIM-related ILD.

17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin

Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α–null or ER-β–null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.     

First clinical evaluation of a new innovative ureteral access sheath (Re-Trace™): a European study

Purpose

The use of a ureteral access sheath (UAS) during flexible retrograde intrarenal surgery (RIRS) has become increasingly popular. Our aim was to evaluate the accessibility of a new UAS device, allowing the transformation of the working guidewire into a safety guidewire.

Methods

A prospective, multicenter study was conducted between January and February 2010 in six European tertiary reference centers. Patients needing flexible RIRS were eligible to participate in the study. In all cases, insertion of the Re-Trace? (12/14Fr, Coloplast, Denmark) was attempted at the beginning of the procedure. Insertion success was defined as placement of the UAS in the lumbar ureter with successful disengagement of the working guidewire, which turned into a safety guidewire. Influence of gender and pre-stenting status was analyzed by univariate analysis.

Results

137 UASs were used in 75 male and 62 female patients. 25.5 % of ureters were pre-stented: men were 2.17 more often pre-stented than women. The overall Re-Trace? insertion rate was 82.5 %. Success rate was not significantly different between men and women (77.3 vs. 88.7 %, respectively, p = 0.11). Pre-stenting status did not significantly influence the success rate (p = 0.31). When analyzing the combined influence of pre-stenting status and gender, the worst success rates seemed to be obtained in men without pre-stenting, but no significant differences were found between groups.

Conclusions

Re-Trace? UAS showed good overall insertion rates. This evaluation validated the new concept of guidewire disengagement: A single wire automatically switches from working to safety role.     

Comparison of antibody and cell-mediated immune responses of foals and adult horses after vaccination with live Mycobacterium bovis BCG

Background

Equine neonates have reduced humoral and cell-mediated immune responses compared to adult horses after administration of killed vaccines. As a basis for this study, we hypothesized that newborn foals can mount strong immune responses after vaccination with live Mycobacterium bovis BCG.

Methods

Healthy 4-day-old foals (n = 7), 4-month-old foals (n = 7) and adult horses (n = 6) were vaccinated once with live M. bovis BCG. Age-matched animals (n = 5 per group) were used as unvaccinated controls. Relative vaccine-specific immunoglobulin concentrations and whole blood mRNA expression of IFN-γ, IL-4, and IL-10 were measured prior to and 2, 4, 6, and 8 weeks after vaccination. Eight weeks after vaccination, delayed type hypersensitivity (DTH) responses were assessed by measuring the increase in double skin thickness after intradermal injection of purified protein derivative.

Results

Both groups of foals and adult horses responded with a significant increase in vaccine-specific total IgG, IgGa, IgGc, IgG(T), and IgM concentrations. In contrast, only adult horses mounted significant IgGb responses. Vaccine-specific concentrations of total IgG and IgGa were significantly higher in adult horses than in 4-day-old foals whereas IgGc responses were significantly higher in 4-day-old foals than in the other two age groups. Adult horses had significantly higher basal IFN-γ and IL-4 mRNA expression than both groups of foals but vaccination with M. bovis BCG did not significantly increase expression of these cytokines, regardless of age group. Immunized horses had significantly higher DTH responses than age-matched unvaccinated controls. DTH responses were significantly greater in both groups of vaccinated foals than in vaccinated adult horses.

Conclusion

Despite a naïve immune system, newborn foals have the ability to mount robust antibody and cell-mediated immune responses to M. bovis BCG.     

Comparison of the effects of EM-652 (SCH57068), tamoxifen, toremifene, droloxifene, idoxifene, GW-5638 and raloxifene on the growth of human ZR-75-1 breast tumors in nude mice

EM-652 exerts pure antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the antiestrogen most widely used for the treatment of breast cancer, exerts mixed antiestrogenic-estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 microg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652-treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652-treated group. The agonistic and antagonistic actions of each antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease.     

Proteinases as hormone-like signal messengers

Proteinases like thrombin and trypsin, long known for their ability to activate the coagulation cascade or to act as hormone-processing enzymes, are now recognised as hormone-like regulators of cell function. These serine proteinases activate cell signalling by triggering a novel four-member family of G-protein-coupled receptors, termed Proteinase-Activated Receptors (PARs). This review article summarises historically the discovery of PARs as well as their unique mechanism of activation and outlines a number of different pathophysiological settings in which PARs can act to regulate cell and tissue function. PARs can be seen to play a role in pathophysiological processes ranging from inflammation and pain to cardiovascular disease and cancer. Apart from activating PARs to cause their physiological effects in tissues, proteinases can also mediate cell signalling via a number of other mechanisms, including the activation of growth factor receptors, like the one for insulin. Therefore, this article also describes the non-PAR mechanisms whereby proteinases can have hormone-like actions in cells and tissues.     

Nicotine injected into the antennal lobes induces a rapid modulation of sucrose threshold and improves short-term memory in the honeybee Apis mellifera

In honeybee, although it is known that the food perception and the olfactory memory can be modulated by many environmental and biochemical factors, nothing is known on the effects of nicotine on these processes. Using microinjections of nicotine in the antennal lobes, we show that nicotine at 10(-3) M and 10(-4) M but not at 10(-5) M induced an increase of sucrose sensitivity and that post-training injection of 10(-5) M nicotine improved retention of olfactory learning. These results demonstrate that potentiation of the cholinergic system in the honeybee enhances sucrose perception and facilitates olfactory memory.     

Subject Index, Volume 81

Volume Contents

Subject Index, Volume 81