Interferon-alpha and -beta differentially regulate osteoclastogenesis: role of differential induction of chemokine CXCL11 expression

In humans, type I interferon (IFN) is a family of 17 cytokines, among which the alpha subtypes and the beta subtype are differentially expressed. It has been suggested that IFN-beta activates a specific signaling cascade in addition to those activated by all type I IFNs. Nevertheless, no true biological relevance for a differential activity of alpha and beta IFN subtypes has been identified so far. Because type I IFNs are critical for the regulation of osteoclastogenesis in mice, we have compared the effect of IFN-alpha2 and IFN-beta on the differentiation of human monocytes into osteoclasts. Primary monocytes undergoing osteoclastic differentiation are highly and equally sensitive to both alpha2 and beta IFNs as determined by measuring the induction levels of several IFN-stimulated genes. However, IFN-beta was 100-fold more potent than the alpha2 subtype at inhibiting osteoclastogenesis. Expression profiling of the genes differentially regulated by IFN-alpha2 and IFN-beta in this cellular system revealed the chemokine CXCL11 as the only IFN-induced gene differentially up-regulated by IFN-beta. We show that recombinant CXCL11 by itself inhibits osteoclastic differentiation. These results indicate that autocrine-acting CXCL11 mediates, at least in part, the regulations of osteoclastogenesis by type I IFNs.     

Anti-factor VIII antibodies of hemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restriction

A significant proportion of hemophilia A patients receiving transfusions of factor VIII (FVIII) develop a specific antibody response towards FVIII. These antibodies are usually detected by assays in which they inhibit the function of the molecule, such as the Bethesda clotting test. We have prepared anti-FVIII antibodies by specific immunoadsorption from the plasma of four hemophiliacs with stable inhibitor levels. The isotypic distribution of such antibodies was determined and their capacity to bind to insolubilized FVIII was compared with their inhibitory activity in two functional assays, namely, the Bethesda assay and a chromogenic assay. In addition, the FVIII epitope specificity was determined by competition with monoclonal antibodies for the binding to insolubilized FVIII. We show here that (1) anti-FVIII antibodies are not isotypically restricted; thus, a significant proportion of specific IgG2 was found; (2) antibodies are frequently directed towards epitopes of FVIII that are not directly involved in the function of the molecule and therefore escape detection in the Bethesda method or chromogenic assay; and (3) each patient shows a unique pattern of FVIII epitope recognition. We conclude that evaluation of anti-FVIII antibodies by a functional method does not provide an accurate evaluation of the specific antibody response. These findings have important implications for the comparison of the immunogenicity of FVIII molecules produced by different technologies and for the development of methods to control anti-FVIII antibody production.     

13C/31P NMR studies of glucose transport in human skeletal muscle

The muscle intracellular (IC) free glucose concentration and the rate of muscle glycogen synthesis were measured by using in vivo ¹³C and ³¹P NMR spectroscopy in normal volunteers under hyperinsulinemic (≈300 pM) clamp conditions at the following three plasma glucose levels: euglycemia (≈6 mM), mild (≈10 mM), and high (≈16 mM) hyperglycemia. In keeping with biopsy studies, muscle IC free glucose concentration at euglycemia (−0.03 ± 0.03 mmol/kg of muscle, mean ± SEM, n = 10) was not statistically different from zero. A small but statistically significant amount of IC free glucose was observed during mild and high hyperglycemia: 0.15 ± 0.08 (n = 5) and 0.43 ± 0.20 mmol/kg of muscle (n = 5), respectively. Muscle glycogen synthesis rate, in mmol per kg of muscle per min, was 111 ± 11 at euglycemia (n = 10), 263 ± 29 during mild hyperglycemia (n = 5), and 338 ± 42 during high hyperglycemia (n = 5), these three rates being significantly different from each other. As previous in vitro and in vivo studies, these rates suggest a K_m (concentration at which unidirectional glucose transport reaches half-maximal rate) of the muscle glucose transport system in the 15–25 mM range under hyperinsulinemic conditions. The low concentrations of muscle IC free glucose observed under hyperinsulinemic conditions were interpreted, with this estimate and in the framework of metabolic control theory, as glucose transport being the predominant step controlling muscle glucose flux not only at euglycemia but also during hyperglycemia.     

Impact of socio-economic status on hospital length of stay following injury: a multicenter cohort study

Background

Injury is second only to cardiovascular disease in terms of acute care costs in North America. One key to improving injury care efficiency is to generate knowledge on the determinants of resource use. Socio-economic status (SES) is a documented risk factor for injury severity and mortality but its impact on length of stay (LOS) for injury admissions is unknown. This study aimed to examine the relationship between SES and LOS following injury.This multicenter retrospective cohort study was based on adults discharged alive from any trauma center (2007–2012; 57 hospitals; 65,486 patients) in a Canadian integrated provincial trauma system. SES was determined using ecological indices of material and social deprivation. Mean differences in LOS adjusted for age, gender, comorbidities, and injury severity were generated using multivariate linear regression.

Results

Mean LOS was 13.5 days. Patients in the highest quintile of material/social deprivation had a mean LOS 0.5 days (95 % CI 0.1-0.9)/1.4 days (1.1-1.8) longer than those in the lowest quintile. Patients in the highest quintiles of both social and material deprivation had a mean LOS 2.6 days (1.8-3.5) longer than those in the lowest quintiles.

Conclusions

Results suggest that patients admitted for traumatic injury who suffer from high social and/or material deprivation have longer acute care LOS in a universal-access health care system. The reasons behind observed differences need to be further explored but may indicate that discharge planning should take patient SES into consideration.

     

Predictors of Energy Compensation during Exercise Interventions: A Systematic Review

Weight loss from exercise-induced energy deficits is usually less than expected. The objective of this systematic review was to investigate predictors of energy compensation, which is defined as body energy changes (fat mass and fat-free mass) over the total amount of exercise energy expenditure. A search was conducted in multiple databases without date limits. Of 4745 studies found, 61 were included in this systematic review with a total of 928 subjects. The overall mean energy compensation was 18% ± 93%. The analyses indicated that 48% of the variance of energy compensation is explained by the interaction between initial fat mass, age and duration of exercise interventions. Sex, frequency, intensity and dose of exercise energy expenditure were not significant predictors of energy compensation. The fitted model suggested that for a shorter study duration, lower energy compensation was observed in younger individuals with higher initial fat mass (FM). In contrast, higher energy compensation was noted for younger individuals with lower initial FM. From 25 weeks onward, energy compensation was no longer different for these predictors. For studies of longer duration (about 80 weeks), the energy compensation approached 84%. Lower energy compensation occurs with short-term exercise, and a much higher level of energy compensation accompanies long-term exercise interventions.     

Proto-oncogene c-mpl is involved in spontaneous megakaryocytopoiesis in myeloproliferative disorders

Spontaneous megakaryocytic colonies (CFU-MK) formation without the addition of Meg-CSA in myeloproliferative disorders (MPD) has been reported by many laboratories. The mechanism by which this occurs is still unknown. In our previous work we have found that the spontaneous colonies persisted in serum-free agar culture although the colony cells were smaller and the colony numbers fewer than in plasma clot culture and that monoclonal antibodies against IL3, IL6 and GM-CSF had no inhibitory effect on spontaneous CFU-MK in both semi-solid cultures. Recently, proto-oncogene c-mpl and c-mpl ligand, thrombopoietin (TPO), have been shown to specifically participate in the regulation of normal human megakaryocytopoiesis. In order to test the hypothesis that c-mpl c-mpl ligand pathway is involved in the spontaneous growth of megakaryocyte progenitors, we investigated mRNA expressions of c-mpl and TPO in cells grown in serum-free liquid culture using RT-PCR. The c-mpl expression was detected in the cultured cells from all nine patients (six with ET, two with PV, one with PMF) who had spontaneous CFU-MK in clonal assays. However, none of the patients expressed TPO mRNA in these cells. Pre-incubation of nonadherent mononuclear cells with thioester-modified antisense oligodeoxynucleotide to c-mpl at a concentration of 6μ M significantly decreased the cloning efficiency of spontaneous megakaryocyte growth by 42.5% ( P <0.05) in plasma clot assay (seven with ET, one with PV) and 69.6% ( P <0.05) in serum-free agar culture (six with ET, one with PV). In control experiments the introduction of a scrambled oligomer to antisense oligodeoxynucleotide had no such effect on spontaneous colony formation. These results indicate that c-mpl exerts an important effect in the growth of spontaneous megakaryocytopoiesis in MPD.     

Outcomes in a Community-Based Intensive Cardiac Rehabilitation Program: Comparison with Hospital-Based and Academic Programs

Background

The purpose of this study was to test the hypothesis that a community-based intensive cardiac rehabilitation program could produce positive changes in risk factor profile and outcomes in an at-risk population.

Serial left ventricular adaptations in world-class professional cyclists: implications for disease screening and follow-up

OBJECTIVES: The purpose of this research was to study long-term left ventricular (LV) adaptations in very-high-level endurance athletes. BACKGROUND: Knowledge of cardiac changes in athletes, who are at particularly high risk of sudden cardiac death, is mandatory to detect hypertrophic cardiomyopathy (HCM) or dilated (DCM) cardiomyopathy. METHODS: We carried out echocardiographic examinations on 286 cyclists (group A) and 52 matched sedentary volunteers (group C); 148 cyclists participated in the 1995 "Tour de France" race (group A1), 138 in the 1998 race (group A2), and 37 in both (group B). RESULTS: In groups A, A1, A2, and C, respectively, diastolic left ventricular diameter (LVID) was 60.1 +/- 3.9 mm, 59.2 +/- 3.8 mm, 61.0 +/- 3.9 mm, and 49.0 +/- 4.3 mm (A vs. C and A1 vs. A2, p < 0.0001), and maximal wall thickness (WT) was 11.1 +/- 1.3 mm, 11.6 +/- 1.3 mm, 10.6 +/- 1.1 mm, and 8.6 +/- 1.0 mm (A vs. C and A1 vs. A2, p < 0.0001). Among group A, 147 (51.4%) had LVID >60 mm; 17 of them had also a below normal (<52%) left ventricular ejection fraction (LVEF). Wall thickness exceeded 13 mm in 25 athletes (8.7%) (always <15 mm), 23 with LVID >55 mm. In group B, LVID increased (58.3 +/- 4.8 mm to 60.3 +/- 4.2 mm, p < 0.001) and WT decreased (11.8 +/- 1.2 mm to 10.8 +/- 1.2 mm, p < 0.001) with time. CONCLUSIONS: Over one-half of these athletes exhibited unusual LV dilation, along with a reduced LVEF in 11.6% (17 of 147), compatible with the diagnosis of DCM. Increased WT was less common (always <15 mm) and scarce without LV dilation (<1%), eliminating the diagnosis of HCM. Serial examinations showed evidence of further LV dilation along with wall thinning. These results might have important implications for screening in athletes.