alpha-Lipoic acid modulates extracellular matrix and angiogenesis gene expression in non-healing wounds treated with hyperbaric oxygen therapy

alpha-Lipoic acid (LA) has been found previously to accelerate wound repair in patients affected by chronic wounds who underwent hyperbaric oxygen (HBO) therapy. Because proteinases are important in wound repair, we hypothesized that LA may regulate matrix metalloproteinase (MMP) expression in cells that are involved in wound repair. Patients undergoing HBO therapy were double-blind randomized into two groups: the LA group and the placebo group. Gene expression profiles for MMPs and for angiogenesis mediators were evaluated in biopsies collected at the first HBO session, at the seventh HBO session, and after 14 days of HBO treatment. ELISA tests were used to validate microarray expression of selected genes. LA supplementation in combination with HBO therapy downregulated the inflammatory cytokines and the growth factors which, in turn, affect MMPs expression. The disruption of the positive autocrine feedback loops that maintain the chronic wound state promotes progression of the healing process.     

Poor survival of ABG I hip prosthesis in younger patients

Background: Hydroxyapatite coated (HAC) hip implants have been used in clinical practice for more than two decades. However, the majority of studies have reported only intermediate term outcomes that are not reliable for predicting long-term behavior in all implants. The aim of this study was to determine the performance of HAC total hip arthroplasty in younger patients over a 10-year follow-up period. Methods and Results: This was an observational retrospective study of a 137 consecutive hips with the ABG I prosthesis. Of these, 128 were available for the last investigation. Median duration of follow-up was 10.9 years. The mean age at time of index surgery was 46+/-6.7 years. Probability of implant survival was estimated using the Kaplan-Meier method. The overall 12-year cumulative survival was 0.55 (95% CI, 0.443-0.659). Periprosthetic osteolysis (57 %) was the most frequent reason for failure followed by aseptic loosening (28 %). When only aseptic loosening was included in the analysis, the same figures for cup and stem were 0.873 (95% CI, 0.808-0.938) and 0.992 (95% CI, 0.976- 1.0), respectively. Patients with a smaller cup size were those at high risk for revision due to wear-related complications (odds ratio, OR=4.3; 95% CI, 1.734-10.555). Conclusion: This study reports one of the poorest 12-year survivorship data for cementless acetabular component in the literature. The main reason for premature failure was osteolysis, strongly related to high wear rate of polyethylene.     

Implementation of contact definitions calculated by FEA to describe the healing process of basal implants

Aims: Bone structure around basal implants shows a dual healing mode: direct contact areas manifest primary osteonal remodeling, in the void osteotomy-induced spaces, the repair begins with woven bone formation. This woven bone is later converted into osteonal bone. The purpose of this study was to develop a model to accurately represent the interface between bone and basal implant throughout the healing process. The model was applied to the biological scenario of changing load distribution in a basal implant system over time. Methods: Computations were made through finite element analysis using multiple models with changing boneimplant contact definitions which reflected the dynamic nature of the interface throughout the bony healing process. Five stages of bony healing were calculated taking into account the changes in mineral content of bone in the vicinity of the load transmitting implant surfaces. Results: As the bony integration of basal implants proceeds during healing, peak stresses within the metal structure shift geographically. While bony repair may still weaken osteonal bone, woven bone has already matured. This leads to changes in the load distribution between and within the direct contact areas, and bone areas which make later contact with implant. Conclusions: This study shows that basal implants undergo an intrinsic shift of maximum stress regions during osseointegration. Fatigue testing methods in the case of basal implants must therefore take into account this gradual shift from early healing phase until full osseointegration is achieved.     

Kit- and Fc epsilonRI-induced differential phosphorylation of the transmembrane adaptor molecule NTAL/LAB/LAT2 allows flexibility in its scaffolding function in mast cells

The transmembrane adaptor protein (TRAP), NTAL, is phosphorylated in mast cells following FcvarepsilonRI aggregation whereby it cooperates with LAT to induce degranulation. The Kit ligand, stem cell factor (SCF), enhances antigen-induced degranulation and this also appears to be NTAL-dependent. However, Kit and FcvarepsilonRI appear to utilize different mechanisms to induce NTAL phosphorylation. Thus, we examined whether the responsible kinases selectively phosphorylated distinct tyrosines in NTAL and explored the implications for downstream signaling. Whereas FcvarepsilonRI required Lyn and Syk for NTAL phosphorylation, Kit appeared to directly phosphorylate NTAL. Furthermore, co-transfection studies with NTAL constructs revealed that Lyn, Syk, and Kit phosphorylate different tyrosines in NTAL. The tyrosines principally phosphorylated by Syk were recognized as Grb2-binding sites, whereas Lyn and Kit phosphorylated other tyrosines, both inside and outside of these motifs. Pull down studies revealed that PLCgamma1 associated with the two terminal Syk-phosphorylated Grb2-binding sites, which would help to explain the observed decrease in antigen-induced calcium signal and degranulation in NTAL-knock down-human mast cells. The observations reported herein support the conclusion that NTAL may be differentially utilized by specific receptors for relaying alternative signals and this suggests a flexibility in the function of TRAPs not previously appreciated.     

Imidazolidin-4-one peptidomimetic derivatives of primaquine: synthesis and antimalarial activity

The synthesis of imidazolidin-4-one derivatives of primaquine containing the five-membered ring at the C-terminus of a dipeptide backbone coupled to the parent drug is described. These peptidomimetic derivatives were active against a chloroquine-resistant Plasmodium falciparum strain and inhibited the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The novel imidazolidin-4-ones are extremely stable, both in human plasma and in pH 7.4 buffer, as a result of N¹-acylation. Thus, ‘internal’ imidazolidin-4-ones derived from dipeptidyl 8-aminoquinolines represent a new entry in antimalarial structure–activity relationships.