Propranolol Promotes Bone Formation and Limits Resorption Through Novel Mechanisms During Anabolic Parathyroid Hormone Treatment in Female C57BL/6J Mice

Although the nonselective β-blocker, propranolol, improves bone density with parathyroid hormone (PTH) treatment in mice, the mechanism of this effect is unclear. To address this, we used a combination of in vitro and in vivo approaches to address how propranolol influences bone remodeling in the context of PTH treatment. In female C57BL/6J mice, intermittent PTH and propranolol administration had complementary effects in the trabecular bone of the distal femur and fifth lumbar vertebra (L₅), with combination treatment achieving microarchitectural parameters beyond that of PTH alone. Combined treatment improved the serum bone formation marker, procollagen type 1 N propeptide (P1NP), but did not impact other histomorphometric parameters relating to osteoblast function at the L₅. In vitro, propranolol amplified the acute, PTH-induced, intracellular calcium signal in osteoblast-like cells. The most striking finding, however, was suppression of PTH-induced bone resorption. Despite this, PTH-induced receptor activator of nuclear factor κ-B ligand (RANKL) mRNA and protein levels were unaltered by propranolol, which led us to hypothesize that propranolol could act directly on osteoclasts. Using in situ methods, we found Adrb2 expression in osteoclasts in vivo, suggesting β-blockers may directly impact osteoclasts. Consistent with this, we found propranolol directly suppresses osteoclast differentiation in vitro. Taken together, this work suggests a strong anti-osteoclastic effect of nonselective β-blockers in vivo, indicating that combining propranolol with PTH could be beneficial to patients with extremely low bone density. © 2022 American Society for Bone and Mineral Research (ASBMR).     

External fixators in the treatment of midshaft clavicle non-unions: a systematic review

Non- or mal-union of the clavicle is reported to occur in up to 15 % of conservatively treated fractures: the purpose of this systematic review is to examine the evidence for the use of external fixation in the treatment of clavicular non-union. We performed a search of MEDLINE and Embase, including all papers using external fixators for the treatment of clavicular non-union. Four papers satisfied our eligibility criteria: three case series and one case–control study. Level of evidence and quality assessment scoring were performed using published methods. Due to the heterogeneity of the study populations and interventions, no attempt at meta-analysis was made. External fixation in hypertrophic non-union of the clavicle, but not atrophic non-union, appears to be a reasonable treatment option. A pragmatic, multicentre, randomised controlled trial comparing external fixation and open reduction internal fixation in the treatment of hypertrophic non-union of the clavicle would be valuable.     

Infective endocarditis in the billowing mitral leaflet syndrome.

Ten patients with the billowing mitral leaflet syndrome complicated by infective endocarditis are reported. Two patients had a non-ejection systolic click and 8 had both a non-ejection systolic click and a late systolic murmur. These auscultatory features were difficult to detect in 4 instances in that they were intermittent, soft, or brought out only with postural change. Seven patients were unaware of their cardiac lesions. A low grade pyrexia was present in all 10 patients. Four patients presented with clinical features caused by reversible neurological lesions. Blood cultures were positive in all patients, with Staphylococcus albus the infecting organism in 6. Antibiotic therapy was successful with significant mitral regurgitation supervening in only one instance. The importance of the billowing leaflet as a potential site of infective endocarditis is emphasized. It seems that antibiotic prophylaxis is indicated at times of increased risk of infection in subjects with a non-ejection systolic click or a late systolic murmur.     

Proliferation of myeloid progenitor cells in human long-term bone marrow cultures is stimulated by interleukin-1 beta

To study the effect of interleukin-1 (IL-1) beta on the proliferation of hematopoietic progenitor cells (HPC) in long-term bone marrow cultures (LTBMC), stromal cell layers were established from normal human bone marrow. Autologous cryopreserved mononuclear phagocyte- and T-lymphocyte-depleted bone marrow cells were reinoculated on the stromal layers in fresh culture medium, with or without the addition of human IL-1 beta (30 U/mL). Once a week, half of the culture supernatant was replaced with fresh culture medium with or without IL-1, and all nonadherent cells were returned to the flasks. At weekly intervals during a period of 5 weeks, one culture was sacrificed to determine the total number of cells and hematopoietic progenitor cells, present in the adherent and the nonadherent cell fractions. In IL-1-stimulated cultures, the number of cells recovered during a period of 5 weeks exceeded the number of cells in unstimulated control cultures by 1.5 times. This difference was attributed to a twofold increase in the number of adherent cells. The number of HPC recovered from IL-1- stimulated cultures was not different from that recovered from controls. The levels of colony-stimulating activity (CSA) in supernatants from IL-1-stimulated cultures were significantly higher than those in supernatants from control cultures. These results indicate that IL-1 enhances the recovery of cells in LTBMC by stimulating the proliferation of HPC with the concurrent release of CSA from stromal cells, without diminishing the number of HPC.     

Interferon-alpha stimulates production of interleukin-10 in activated CD4+ T cells and monocytes

In the present study, we investigated the effect of interferon-alpha (IFN-alpha) on the expression of interleukin-10 (IL-10) mRNA and protein synthesis in human monocytes and CD4+ T cells. In mononuclear cells, IFN-alpha induced expression of IL-10 mRNA and further enhanced lipopolysaccharide (LPS)-stimulated IL-10 expression. In purified monocytes, a strong expression of IL-10 mRNA induced by LPS was not further enhanced by IFN-alpha. In highly purified CD4+ T cells, IFN- alpha upregulated IL-10 mRNA upon activation with phytohemagglutinin and phorbol myristate acetate. In purified monocytes, an effect of IFN- alpha on IL-10 protein synthesis was dependent on costimulation with LPS. Maximal stimulation of IL-10 protein by IFN-alpha was seen after prolonged incubation periods of 48 to 96 hours, whereas IFN-gamma reduced IL-10 production in the early incubation period. Similar effects of IFN-alpha were observed in CD4+ T cells activated with CD3 and CD28 monoclonal antibodies. Addition of IFN-alpha caused an increase of IL-10 in culture supernatants of activated T-helper cells of more than 100% after 96 hours of incubation. In contrast, other cytokines, including IFN-gamma and IL-4, had no influence on IL-10 secretion stimulated by CD3 and CD28 in CD4+ T cells. In serum samples of IFN-alpha-treated individuals, we failed to detect an influence of cytokine treatment on IL-10 serum levels, confirming the requirement of additional activating signals for IFN-alpha-mediated effects on IL-10 synthesis. In conclusion, IFN-alpha enhances the late induction of IL- 10, which physiologically occurs upon stimulation of monocytes and T cells. Biologically, this effect might enhance the negative-feedback mechanism ascribed to IL-10, which limits inflammatory reactions.     

Low exercise blood pressure and risk of cardiovascular events and all-cause mortality: Systematic review and meta-analysis

Objective

The independent prognostic significance of abnormally low systolic blood pressure (SBP) during exercise stress testing (LowExBP) across different clinical and exercise conditions is unknown. We sought by systematic review and meta-analysis to determine the association between cardiovascular/all-cause outcomes and LowExBP across different patient clinical presentations, exercise modes, exercise intensities and categories of LowExBP.

Methods

Seven online databases were searched for longitudinal studies reporting the association of LowExBP with risk of fatal and non-fatal cardiovascular events and/or all-cause mortality. LowExBP was defined as either: SBP drop below baseline; failure to increase >10 mmHg from baseline or; lowest SBP quantile among reporting studies.

Results

After review of 13,257 studies, 19 that adjusted for resting SBP were included in the meta-analysis, with a total of 45,895 participants (average follow-up, 4.4 ± 3.0 years). For the whole population, LowExBP was associated with increased risk for fatal and non-fatal cardiovascular events and all-cause mortality (hazard ratio [HR]: 2.01, 95% confidence interval [CI]: 1.59–2.53, p < 0.001). In continuous analyses, a 10 mmHg decrease in exercise SBP was associated with higher risk (n = 9 HR: 1.13, 95% CI: 1.06–1.20, p < 0.001). LowExBP was associated with increased risk regardless of clinical presentation (coronary artery disease, heart failure, hypertrophic cardiomyopathy or peripheral artery disease), exercise mode (treadmill or bike), exercise intensity (moderate or maximal), or LowExBP category (all p < 0.05). However, bias toward positive results was apparent (Eggers test p < 0.001 and p = 0.009).

Conclusion

Our data show that irrespective of clinical or exercise conditions, LowExBP independently predicts fatal and non-fatal cardiovascular events and all-cause mortality.     

Potential Role of Direct Oral Anticoagulants in the Management of Heparin-induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a rare, potentially life-threatening condition secondary to unfractionated heparin or low molecular weight heparin exposure. This immune-mediated drug reaction manifests as thrombocytopenia with a paradoxical hypercoagulable state that can result in life-threatening thrombosis. It is imperative to ensure cessation of heparin-based products as soon as HIT is identified. Traditional treatment options include argatroban, bivalirudin, fondaparinux, and danaparoid with a transition to warfarin upon platelet recovery. These anticoagulants are notwithstanding limitations including parenteral administration and routine laboratory monitoring leading to prolonged hospitalizations, emphasizing the need for new therapies. Direct oral anticoagulants (DOACs) have been increasingly investigated for the management of HIT and may overcome the aforementioned challenges of current therapies. The objective of this narrative review is to summarize the current HIT guidelines, discuss limitations to contemporary treatment options, provide insight into the emerging evidence for the DOACs rivaroxaban, apixaban, and dabigatran, and conclude with a clinical summary for their use in this setting. The PubMed, Google Scholar, and MEDLINE databases were searched for peer-reviewed literature from January 1, 2012, to June 31, 2018. Twenty-seven articles met inclusion criteria for review: 1 prospective trial, 5 retrospective cohort studies, and 21 case reports totaling 104 patients treated with a DOAC for HIT. The DOACs prevented new and recurrent thrombosis in 98% (n=102) of cases, and bleeding complications occurred in 3% (n=3). While current literature remains limited, it is suggestive of a potential role of DOACs for HIT, which has led to their integration into the 2018 American Society Hematology Guidelines with a conditional recommendation.     

IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis

Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Using murine models we demonstrate a role for interleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanistically, we identify IL-13 release from type 2 innate lymphoid cells (ILC2) as sufficient to drive collagen deposition in the lungs of challenged mice and suggest this as a potential mechanism through which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expression of IL-25 and also observe a population ILC2 in the lungs of idiopathic pulmonary fibrosis patients. Collectively, we present an innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2, that occurs independently of T-cell–mediated antigen-specific immune responses. These results suggest the potential of therapeutically targeting IL-25 and ILC2 for the treatment of human fibrotic diseases.Disease conditions associated with pulmonary fibrosis are often progressive and have a poor long-term prognosis (1). In the context of developing new treatments for pulmonary fibrosis, the cytokines associated with the pathogenic milieu that can lead to aberrant extracellular matrix deposition are key targets, in particular interleukin (IL)-13, TGF-β, and, more recently, IL-17A (2). However, to develop more effective therapeutics for fibrotic lung diseases a greater understanding of the pathogenesis and the underlying mechanisms that lead to pulmonary fibrosis is needed (3, 4).The cytokine IL-13 was first implicated in fibrosis using profibrotic eggs from the type 2 cytokine-inducing pathogen Schistosoma mansoni, in the presence of a soluble IL-13Rα2-Fc fusion protein (5) and in Il13^−/− mice (6). IL-13 is now widely linked to a range of fibrotic conditions (7) including asthma, where IL-13 is being targeted as a therapy (8). In the context of the cellular source of IL-13 in the generation of fibrosis, CD4⁺ T helper (h) 2 cells are implicated (9). However, more recently innate lymphoid cells (ILC) are emerging as an important source of IL-13 (10, 11). In this context, the type 2 cytokine IL-25 is implicated in the generation of the recently identified IL-13–expressing ILC, termed ILC2 (11–14).Recent studies have implicated IL-25 and ILC2 in the pathogenesis of pulmonary conditions in both murine models and human conditions such as allergic asthma (12, 13, 15, 16). In murine studies intranasal administration of IL-25 results in evidence of pulmonary tissue remodeling including development of perivascular fibrosis, and intratracheal administration results in increased pulmonary Th2 cytokines and airways hyper-reactivity (AHR) (17, 18), whereas blocking IL-25 reduces AHR severity (19). Herein we describe a potential role for IL-25 in the generation of pulmonary fibrosis in experimental mouse models, via the activation of IL-13–producing ILC2. We also observe increases in both IL-25 and ILC2 in the lung of patients with idiopathic pulmonary fibrosis (IPF). These data suggest unique mechanisms for the generation of pulmonary fibrosis and identify an interesting area for further research on the role of IL-25 and ILC2 in the treatment of pulmonary fibrosis.     

Enhanced Cytotoxicity through Conjugation of a “Clickable” Luminescent Re(I) Complex to a Cell-Penetrating Lipopeptide

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