Zoledronic Acid in Reducing Clinical Fracture and Mortality after Hip Fracture.

BACKGROUND: Mortality is increased after a hip fracture, and strategies that improve outcomes are needed. METHODS: In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. RESULTS: The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction (P = 0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P = 0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P = 0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic-acid group (P = 0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS: An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and improved survival. (ClinicalTrials.gov number, NCT00046254.).

A novel method of dynamic culture surface expansion improves mesenchymal stem cell proliferation and phenotype.

Repeated passaging in conventional cell culture reduces pluripotency and proliferation capacity of human mesenchymal stem cells (MSC). We introduce an innovative cell culture method whereby the culture surface is dynamically enlarged during cell proliferation. This approach maintains constantly high cell density while preventing contact inhibition of growth. A highly elastic culture surface was enlarged in steps of 5% over the course of a 20-day culture period to 800% of the initial surface area. Nine weeks of dynamic expansion culture produced 10-fold more MSC compared with conventional culture, with one-third the number of trypsin passages. After 9 weeks, MSC continued to proliferate under dynamic expansion but ceased to grow in conventional culture. Dynamic expansion culture fully retained the multipotent character of MSC, which could be induced to differentiate into adipogenic, chondrogenic, osteogenic, and myogenic lineages. Development of an undesired fibrogenic myofibroblast phenotype was suppressed. Hence, our novel method can rapidly provide the high number of autologous, multipotent, and nonfibrogenic MSC needed for successful regenerative medicine.

Juvenile arthritis patients report favorable subjective outcomes of hip arthroplasty despite poor standard outcome scores.

We evaluated midterm patient-reported outcomes and satisfaction with total hip arthroplasty in patients who had severe juvenile idiopathic arthritis. Thirty-one patients (49 hips), with a mean age of 29 years (range, 16-43 years), reported low hip pain and stiffness at follow-up (mean, 7 years; range, 3-17 years). Up to 92% were satisfied with their ability to perform various activities; 96% were satisfied with pain relief. A mean postoperative flexion arc of 96° was observed. Final 36-Item Short Form Health Survey, EuroQol in 5 dimensions, Western Ontario and McMaster Universities Arthritis Index, and Harris Hip scores were lower than reference populations, particularly for mobility, physical functioning, and social functioning subscores. Young adults with end-stage hip involvement and severe longstanding juvenile idiopathic arthritis expressed high satisfaction with total hip arthroplasty, which improved range of motion, pain, and stiffness, despite poor performance on widely used outcome measures.

Immediate hip spica is as effective as, but more efficient than, flexible intramedullary nailing for femoral shaft fractures in pre-school children.

Flexible intramedullary nailing (FIN) is the gold standard treatment for femur fracture in school-aged children. It has been performed successfully in younger children, although Spica cast immobilisation (SCI) has been the most widely used strategy to date. METHOD: A retrospective analysis was performed between two comparable groups of children aged 1-4 years with a femoral shaft fracture. Two University hospitals, each using specific treatment guidelines, participated in the study: SCI in Group I (Basel, Switzerland) and FIN in Group II (Lausanne, Switzerland). RESULTS: Group I included 19 children with a median age of 26 months (range 12-46 months). Median hospital stay was 1 day (range 0-5 days) and casts were retained for a median duration of 21 days (range 12-29 days). General anaesthesia was used in six children and sedation in four. Skin breakdown secondary to cast irritation occurred in two children (10.5%). The median follow-up was 114 months (range 37-171 months). No significant malunion was noted. Group II included 27 children with a median age of 38.4 months (range 18.7-46.7 months). Median hospital stay was 4 days (range 1-13 days). All children required general anaesthesia for insertion and removal of the nails. Free mobilisation and full weight bearing were allowed at a median of 2 days (range 1-10 days) and 7 days (range 1-30 days), respectively, postoperatively. Nail exteriorisation was noted in three children (11%). The median follow-up was 16.5 months (range 8-172 months). No significant malunion was reported. CONCLUSIONS: Young children with a femoral shaft fracture treated by SCI or FIN had similarly favourable outcomes and complication rates. FIN allowed earlier mobilisation and full weight bearing. Compared to SCI, a greater number of children required general anaesthesia. In a pre-school child with a femoral shaft fracture, immediate SCI applied by a paediatric orthopaedic team following specific guidelines allowed early discharge from hospital with few complications.

Die Behandlung von Acetabulumfrakturen bei geriatrischen Patienten mittels modifizierter Kabelcerclage und primärer Hüfttotalprothese. Erste Ergebnisse [Treatment of acetabular fractures in the elderly with primary total hip arthroplasty and modified cerclage. Early results]

This prospective study addresses early results of the treatment of acute acetabular fractures in elderly patients by total hip arthroplasty and cerclage wiring.Fifteen patients with an average age of 81 years were treated at our institution between February 1998 and December 2000. There were two transverse fractures, eight T-shaped fractures, two transverse fractures with associated posterior wall fracture, two posterior column fractures with associated posterior wall fracture, and one fracture of both columns. Treatment consisted of cerclage wiring of the fracture and primary non-cemented total hip replacement.All of the patients were followed for a mean of 36 months. Although there was one patient with three hip dislocations during the first 10 months after the operation, we found an excellent or good result for the entire group. During this relatively short follow-up period, we have not found a radiological loss of fracture reduction of more than 1 mm or a cup migration of more than 3.2 mm. All of the fractures healed and no loosening of the implant was evident.Primary total hip arthroplasty combined with internal fixation is a valid treatment option for acetabular fractures in the elderly. Preliminary results are convincing, but a bigger patient population and a longer follow-up time are necessary before we are able to draw final conclusions.

MDCT arthrography of the hip: value of the adaptive statistical iterative reconstruction technique and potential for radiation dose reduction.

OBJECTIVE: The purpose of this article is to assess the effect of the adaptive statistical iterative reconstruction (ASIR) technique on image quality in hip MDCT arthrography and to evaluate its potential for reducing radiation dose. SUBJECTS AND METHODS: Thirty-seven patients examined with hip MDCT arthrography were prospectively randomized into three different protocols: one with a regular dose (volume CT dose index [CTDIvol], 38.4 mGy) and two with a reduced dose (CTDIvol, 24.6 or 15.4 mGy). Images were reconstructed using filtered back projection (FBP) and four increasing percentages of ASIR (30%, 50%, 70%, and 90%). Image noise and contrast-to-noise ratio (CNR) were measured. Two musculoskeletal radiologists independently evaluated several anatomic structures and image quality parameters using a 4-point scale. They also jointly assessed acetabular labrum tears and articular cartilage lesions. RESULTS: With decreasing radiation dose level, image noise statistically significantly increased (p=0.0009) and CNR statistically significantly decreased (p=0.001). We also found a statistically significant reduction in noise (p=0.0001) and increase in CNR (p≤0.003) with increasing percentage of ASIR; in addition, we noted statistically significant increases in image quality scores for the labrum and cartilage, subchondral bone, overall diagnostic quality (up to 50% ASIR), and subjective noise (p≤0.04), and statistically significant reductions for the trabecular bone and muscles (p≤0.03). Regardless of the radiation dose level, there were no statistically significant differences in the detection and characterization of labral tears (n=24; p=1) and cartilage lesions (n=40; p≥0.89) depending on the ASIR percentage. CONCLUSION: The use of up to 50% ASIR in hip MDCT arthrography helps to reduce radiation dose by approximately 35-60%, while maintaining diagnostic image quality comparable to that of a regular-dose protocol using FBP.

Comparison of the proliferative activity of neuroblasts from chick embryo cerebral hemispheres of different ages in culture.

Dissociated cerebral hemisphere cells from 4- to 7-day-old chick embryos were cultured either on a collagen or a polylysine substrate in a serum-containing medium. Neurons were characterized by the demonstration of acetylcholinesterase, the presence of D2/N-CAM glycoprotein and neurofilament proteins. The proliferation of neuronal precursor cells was shown by morphological observations, autoradiographic analysis and measurements of [3H]-thymidine incorporation. Neuronal precursors derived from the 6-day-old embryos showed the highest proliferative activity. Neuroblast proliferation was found to be dependent on the culture substrates (i.e. polylysine or collagen), which yielded either isolated cells or cell aggregates, and the latter favored the mitogenic effect.

The function of a new regulator of epidermal differentiation, HOP, and pathomechanisms underlying epidermolytic hyperkeratosis

The process of epidermal differentiation involves proliferation, differentiation, migration and maturation of keratinocytes to form an impermeable barrier against water loss and outside environment. It is controlled by highly balanced regulatory machinery, involving many molecules that are still under investigation.Homeobox proteins are involved in body patterning and morphogenesis of organs and are studied as potentially good candidates to regulate this process. In the first project we investigated the role of a protein named HOP which belongs to a group of homeobox proteins. Even if HOP is a small protein almost completely composed of the homeodomain and without DNA binding capacity, it is considered as transcriptional regulator in different tissues. HOP interacts with serum response factor (SRF) and histone deacetylase type 2 (HDAC2). By microarray analysis we found that HOP expression increases in cultured human primary keratinocytes (NHK) which undergo calcium-induced differentiation. HOP protein was localized in granular layer of the epidermis of healthy individuals. Lack of HOP was demonstrated in psoriatic lesions, whereas a strong expression was demonstrated in the lesional skin of patients affected with lichen planus (LP). Since LP is characterized by hypergranulosis while psoriatic lesions by progressive lack of the granular layer, the obtained data indicated that HOP might have a potential function in granular layer of epidermis. To investigate HOP function, we inhibited its expression by using HOP specific StealthRNAi and we overexpressed HOP using lentiviral vectors in differentiating NHK. The conclusion of both experiments indicated that HOP positively regulates the expression of late differentiation markers, such as profilaggrin, loricrin and transglutaminase 1. The in vitro data were next confirmed in vivo using HOP knockout mouse model.The second part of my study involved analysis of mechanisms underlying the pathogenesis of epidermolytic hyperkeratosis (EHK). EHK is a genetic disorder characterized by erythema, skin blistering, keratinocyte hyperproliferation and hyperkeratosis. EHK is caused by mutations in keratin 1 or 10 (K1, K10) which are major structural proteins of differentiated keratinocytes and participate in the cellular scaffold formation. To investigate how the structural proteins carrying mutations alter cellular signaling, we established an in vitro model for EHK by overexpression of one of the most common K10 mutations reported so far (K10R156H), in primary human keratinocytes. In order to mimic the in vivo situation, mutated keratinocytes growing on silicone membranes were subjected to mechanical stretch. We observed strong collapse of KIF in K10R156H keratinocytes when subjected to stretch for 30 minutes. Our data demonstrated stronger activation of p38, a member of MAPK stress signaling pathways, in K10R156H when compared to control cells. We demonstrated also that K10R156H keratinocytes showed an induction of TNF-α and RANTES release in response to stretch.Taken together these studies characterize a novel regulator of epidermal differentiation - HOP and demonstrate new aspects implicated in the pathogenesis of EHK.