Defective implant osseointegration under protein undernutrition: prevention by PTH or pamidronate.

Protein deficiency is associated with impaired titanium osseointegration. We studied whether systemic treatment with PTH or pamidronate could influence the resistance to pull-out of titanium rods implanted into rats proximal tibia under normal and isocaloric low protein intake. PTH or pamidronate prevented the deleterious effects of protein undernutrition on bone microarchitecture close to the implant and on mechanical fixation. PTH even significantly improved implant osseointegration. INTRODUCTION: Protein deficiency is highly prevalent among elderly patients hospitalized in orthopedic wards. Reduced protein intake impairs titanium osseointegration in rats. Whether stimulator of bone formation or inhibitor of bone resorption could improve implant osseointegration under protein deprivation is not known. We studied the effects of systemic treatment with PTH or pamidronate on the resistance to pull-out of titanium rods implanted into rats proximal tibia under normal and isocaloric low protein intake. MATERIALS AND METHODS: We measured the resistance to pull-out 1-mm-diameter titanium rods implanted into the proximal tibias of 49 adult female rats receiving a normal or an isocaloric low protein diet. After 2 wk on either diet, the implants were inserted, and the rats received PTH(1-34), pamidronate or saline vehicle for 8 wk. The tibias were removed for microCT morphometry, followed by the evaluation of pull-out strength. RESULTS: Pull-out strength was lower in rats fed an isocaloric low protein diet compared with rats fed a normal protein intake (-29%). PTH and pamidronate significantly increased pull-out strength in animals fed a normal or a low protein diet, the effect of PTH being of higher magnitude. The PTH- or pamidronate-mediated increase in pull-out strength was associated with significant increases of relative bone volume, bone-to-implant contact, and trabecular thickness, whereas trabecular spacing was reduced, in the vicinity of the implants. CONCLUSIONS: We confirmed that isocaloric low protein intake impairs titanium implant osseointegration. PTH or pamidronate prevented the deleterious effects of protein undernutrition and even significantly improved the implant osseointegration. These results indicate that systemic administration of PTH or pamidronate could be considered for preventing uncemented arthroplasty loosening in protein undernourished patients.     

Effects of beta-blockade on energy metabolism following burns

The purpose of this study was to compare the effects of propranolol administered either by i.v. infusion or by prolonged oral administration (4 days) during the first 3 weeks following burns. The resting metabolic rate (RMR) of 10 non-infected fasting burned patients (TBSA: 28 per cent, range 18-37 per cent) was determined four times consecutively by indirect calorimetry (open circuit hood system) following: (1) i.v. physiological saline; (2) i.v. propranolol infusion (2 micrograms/kg/min following a bolus of 80 micrograms/kg); (3) oral propranolol (40 mg q.i.d. during 4 +/- 1 days); and (4) in control patients. All patients showed large increases in both RMR (144 +/- 2 per cent of reference values) and in urinary catecholamine excretion (three to four times as compared to control values). The infusion of propranolol induced a significant decrease in RMR to 135 +/- 2 per cent and oral propranolol to 129 +/- 3 per cent of reference values. A decrease in lipid oxidation but no change in carbohydrate and protein oxidation were observed during propranolol administration. It is concluded that the decrease in RMR induced by propranolol was not influenced by the route of administration. The magnitude of the decrease in energy expenditure suggests that beta-adrenergic hyperactivity represents only one of the mediators of the hypermetabolic response to burn injury.     

Interleukin 1 alpha and beta in psoriatic skin: enzymoimmunoassay, immunoblot studies and effect of systemic retinoids

Interleukin 1 alpha (IL-1 alpha) and interleukin 1 beta (IL-1 beta) proteins were studied by enzymoimmunoassay (EIA) and Immunoblot analysis in the 10,000 g supernatant of normal and psoriatic (lesional and nonlesional) human skin specimens. By EIA IL-1 alpha was the principal form detected in all the specimens, which contrasts with the predominance of IL-1 beta in human blood monocytes. In psoriatic plaques relatively less IL-1 alpha and more IL-1 beta were detected. On Immunoblot analysis the mature form (17 kD) was not detected in normal skin, which showed only 52-kD immunoreactive forms. In contrast the 17-kD form was found in psoriatic skin. This indicates either a distinct processing of IL-1 molecules or a contribution of inflammatory cells infiltration to the IL-1 pool in psoriatic plaques. During systemic retinoids therapy the amount of both IL-1 species decreased in lesional and nonlesional psoriatic skin.     

Human Th1 cells preferentially induce interleukin (IL)-1β while Th2 cells induce IL-1 receptor antagonist production upon cell/cell contact with monocytes

The role of human T cells in the induction and regulation, upon cell/cell contact, of inflammatory responses by monocytic cells was investigated. The production of interleukin (IL)-1β and IL-1 receptor antagonist (IL-1Ra) by the monocytic THP-1 cell line was measured upon contact with either Th1 or Th2 cell clones. CD4⁺ T cell clones specific for purified protein derivative of Mycobacterium tuberculosis, predominantly Th1 [high interferon (IFN)-γ and low IL-4 producers], or tetanus toxoid, predominantly Th2 (low IFN-γ and high IL-4 producers), were generated. Cell membranes from antigen-stimulated, but not from resting T cell clones induced dose-dependent cytokine production by THP-1 cells. Th1 clones induced higher levels of IL-1β production (484–806 pg/ml) than did Th2 clones (21–114 pg/ml). In contrast, Th1 clones induced lower levels of IL-1Ra (0.9–7.8 ng/ml) than did Th2 clones (7.0–49.6 ng/ml). Similar results were obtained when T cell clones were activated by cross-linked CD3 and CD28. IL-1β production by THP-1 cells correlated with IFN-γ production by T cell clones but was unaffected by IFN-γ neutralization. IL-1Ra production by THP-1 cells correlated with IL-4 production by T cells and was partially inhibited by IL-4 neutralization. These data indicate that activated Th1 and Th2 cells express different molecules on the cell surface able to induce distinct pro-inflammatory (IL-1β) or anti-inflammatory (IL-1Ra) responses in monocytes. This differential induction of molecules with opposite effects on inflammation stresses the functional heterogeneity in CD4⁺ T cells.     

Tumour necrosis factor soluble receptors behave as acute phase reactants following surgery in patients with rheumatoid arthritis, chronic osteomyelitis and osteoarthritis.

Tumour necrosis factor-alpha (TNF-alpha) is involved in diverse biological processes including immune and inflammatory reactions and the response to surgical stress. Two soluble TNF receptor protein fragments, TNF-sR55 (from the p55 kD TNF receptor) and TNF-sR75 (from the p75 kD TNF receptor), are released by cells during inflammation and may modulate the e effects of TNF-alpha. We have studied the kinetics of secretion of TNF-alpha, TNF-sR55 and TNF-sR75 in the sera of patients with rheumatoid arthritis (RA) and control subjects with osteoarthritis (OA) or chronic osteomyelitis (OM) before and after major surgery. Significantly higher pre-operative levels of TNF-sR55 and TNF-sR75 were found in RA and OM as compared with OA (P < 0.02). Following surgery, TNF-sR55 increased within 24 h in RA, OM and OA (P < 0.05), whereas TNF-sR75 increased significantly only in OM and OA patients (P < 0.05). By contrast, no TNF-alpha was detectable before and after surgery in any of the subjects, but this may have been due to impaired detection (by ELISA) of TNF-alpha when it is bound to TNF-sR. These findings suggest that TNF-sR55 and TNF-sR75 may be further markers of the host's reaction to inflammatory insults. They may also play a role in modulating the immune and inflammatory reactions by inhibiting the systemic effects of TNF-alpha.     

CD40-CD40 ligand (CD154) engagement is required but may not be sufficient for human T helper 1 cell induction of interleukin-2- or interleukin-15-driven, contact-dependent, interleukin-1beta production by monocytes

To investigate whether antigen-independent, interleukin-2 (IL-2) or IL-15 activation of polarized T helper (Th) cells would result in contact-dependent activation of monocytes, living Th1 and Th2 cell clones were co-cultured with THP-1 cells or fresh peripheral blood monocytes. Under these conditions IL-1beta production was induced almost exclusively by Th1 cells and was dependent on the presence and dose of IL-2 or IL-15, and on cell-cell contact, as demonstrated by double-chamber cultures. Low levels of IL-1 receptor antagonist (IL-1Ra) were induced by Th1 and higher levels by Th2 cells. IL-10 production was similar in Th1/monocyte and Th2/monocyte co-cultures, thus arguing against preferential down-regulation of IL-1beta production by anti-inflammatory IL-10 in Th2 co-cultures. In addition, IL-4 and IL-10 neutralization did not result in enhanced IL-1beta production in Th2/monocyte co-cultures. Preferential expression on Th1 cells of CD11b correlated with their capacity to induce IL-1beta production by THP-1 cells in the presence of IL-2 or IL-15, but anti-CD11b monoclonal antibody could not inhibit this activity. Blockade of the CD40-CD40 ligand interaction resulted in inhibition of IL-1beta-inducing capacity while IL-1Ra induction was unaffected, a result previously unknown. This differential effect indicates the selective relevance of CD40-CD40 ligand engagement in inflammatory monocyte responses upon activation by T cells. CD40 ligand expression levels did not differ in Th1 and Th2 cell clones, thus indicating that additional, unidentified molecule(s) preferentially expressed by Th1 cells are involved in their IL-1beta induction capacity.     

Presence of autoantibodies to apolipoprotein A-1 in patients with acute coronary syndrome further links autoimmunity to cardiovascular disease

Anti-apolipoprotein A-1 (Apo A-1) autoantibodies were described in autoimmune disorders such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and might be involved in the genesis of arterial and venous thrombotic events. To investigate the presence of these autoantibodies in patients with acute coronary syndrome (ACS) without other features of autoimmunity, we set up an enzyme-linked immunosorbent assay (ELISA) for anti-Apo A-1 antibodies. We used it to investigate their prevalence in ACS as compared to SLE and APS and correlated them to plasma Apo A-1 and serum amyloid A protein (SAA) concentrations. The prevalence of anti-Apo A-1 autoantibodies in the healthy control group was 1% (1/92), but was significantly higher in other groups: 21% (11/53) in ACS group (P=0.001), 13% (12/92) in SLE and/or APS group (P=0.005). Multiple linear regression revealed a significant correlation between plasma Apo A-1 (r=-0.72, P=0.013), plasma SAA concentration (r=0.76, P=0.0066) and anti-Apo A-1 IgG titre in ACS patients. The presence of anti-Apo A-1 autoantibodies in patients with ACS highlights an additional link between autoimmunity, inflammation and atherosclerosis.     

Rheumatoid synovial cell hormone responses modulated by cell-cell interactions

Cellular interactions within the rheumatoid synovium are likely to be responsible for the destructive properties of this tissue. The responses to hormones which regulate connective tissue metabolism may also be influenced by these cell-cell interactions. To determine the effect of cellular interactions on responses to hormones, human peripheral blood mononuclear cells were cocultured with adherent rheumatoid synovial cells. Coculture resulted in a decrease in response to prostaglandin E₂ as assessed by a reduction in the magnitude of the acute prostaglandin-induced cyclic AMP response. In contrast, coculture resulted in an increase in the magnitude of the acute parathyroid hormone-induced cyclic AMP response. The decrease in response to prostaglandin was reversed by the presence of indomethacin during the preincubation, whereas indomethacin had no effect on the cyclic AMP response to parathyroid hormone. Increases in endogenous synovial cell prostaglandin production (stimulated by soluble factors released by the mononuclear cells) accounted for the subsequent decrease in the response to exogenous prostoglandin. The increase in cyclic AMP response to parathyroid hormone could not be explained by a soluble factor and was independent of ambient prostaglandin levels.This work was supported by USPHS grants AM-03564 and AM-07258. This is publication number 942 of the Robert W. Lovett Memorial Unit for the study of Diseases Causing Deformities.J.-M. D. received partial support by grants from Fonds National Suisse de Recherche Scientifique.