James Norton

Biomechanical analysis of blade plate versus locking plate fixation for a proximal humerus fracture: comparison using cadaveric and synthetic humeri.

Objective: To compare the mechanical stability of a fixed-angle blade plate with that of a locking plate in a cadaveric proximal humerus fracture-fixation model subjected to cyclic loading. A secondary objective was to evaluate whether the use of synthetic humerus specimens would replicate significant differences found during cadaveric tests. Design: Mechanical evaluation of constructs in bending and torsion. Setting: Biomechanical laboratory in an academic medical center. Methods: Simulated humeral neck fractures (Orthopaedic Trauma Association (OTA) classification 11A3), in matched-pair cadaveric and synthetic specimens underwent fixation using either a 3.5-mm, 90-degree cannulated LC-Angled Blade Plate or a 3.5-mm LCP Proximal Humerus Locking Plate. Cadaveric specimen constructs were cyclically loaded in bending and torsion; synthetic specimens were tested in torsion. Main Outcome Measure: Humeral shaft-bending displacements and angular rotations for respective cyclic bending loads and axial torques were recorded and compared at repeated cyclic intervals to evaluate construct loosening. Results: Locking-plate constructs exhibited significantly less loosening than blade-plate constructs for torsional loading in cadaveric specimens (P = 0.036). The two types of constructs performed similarly for torsional loading in synthetic specimens (P = 0.100). Under cyclic, closed-bending load conditions in which the plates served as tension members, both types of constructs performed similarly in cadaveric specimens (P = 0.079). Conclusions: For simulated humeral neck fractures subjected to cyclic loading, locking-plate constructs demonstrated significantly greater torsional stability and similar bending stability to blade plates in a cadaveric specimen model. In contrast, these same constructs performed similarly with torsional loading when using synthetic humerus specimens. These results indicate potential advantages for locking-plate fixation. They also indicate that the synthetic specimens tested may not be appropriate for evaluating fixation stability in the humeral head, where cancellous bone fixation predominates.

Fukutin-related protein is essential for mouse muscle, brain and eye development and mutation recapitulates the wide clinical spectrums of dystroglycanopathies

Mutations in fukutin-related protein (FKRP) cause a common subset of muscular dystrophies characterized by aberrant glycosylation of alpha-dystroglycan (α-DG), collectively known as dystroglycanopathies. The clinical variations associated with FKRP mutations range from mild limb-girdle muscular dystrophy type 2I with predominantly muscle phenotypes to severe Walker-Warburg syndrome and muscle-eye-brain disease with striking structural brain and eye defects. In the present study, we have generated animal models and demonstrated that ablation of FKRP functions is embryonic lethal and that the homozygous-null embryos die before reaching E12.5. The homozygous knock-in mouse carrying the missense P448L mutation almost completely lacks functional glycosylation of α-DG in muscles and brain, validating the essential role of FKRP in the functional glycosylation of α-DG. However, the knock-in mouse survives and develops a wide range of structural abnormalities in the central nervous system, characteristics of neuronal migration defects. The brain and eye defects are highly reminiscent of the phenotypes seen in severe dystroglycanopathy patients. In addition, skeletal muscles develop progressive muscular dystrophy. Our results confirm that post-translational modifications of α-DG are essential for normal development of the brain and eyes. In addition, both the mutation itself and the levels of FKRP expression are equally critical for the survival of the animals. The exceptionally wide clinical spectrums recapitulated in the P448L mice also suggest the involvement of other factors in the disease progression. The mutant mouse represents a valuable model to further elucidate the functions of FKRP and develop therapies for FKRP-related muscular dystrophies.

Analysis of meniscal degeneration and meniscal gene expression

BackgroundMenisci play a vital role in load transmission, shock absorption and joint stability. There is increasing evidence suggesting that OA menisci may not merely be bystanders in the disease process of OA. This study sought: 1) to determine the prevalence of meniscal degeneration in OA patients, and 2) to examine gene expression in OA meniscal cells compared to normal meniscal cells.MethodsStudies were approved by our human subjects Institutional Review Board. Menisci and articular cartilage were collected during joint replacement surgery for OA patients and lower limb amputation surgery for osteosarcoma patients (normal control specimens), and graded. Meniscal cells were prepared from these meniscal tissues and expanded in monolayer culture. Differential gene expression in OA meniscal cells and normal meniscal cells was examined using Affymetrix microarray and real time RT-PCR.ResultsThe grades of meniscal degeneration correlated with the grades of articular cartilage degeneration (r = 0.672; P < 0.0001). Many of the genes classified in the biological processes of immune response, inflammatory response, biomineral formation and cell proliferation, including major histocompatibility complex, class II, DP alpha 1 (HLA-DPA1), integrin, beta 2 (ITGB2), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), ankylosis, progressive homolog (ANKH) and fibroblast growth factor 7 (FGF7), were expressed at significantly higher levels in OA meniscal cells compared to normal meniscal cells. Importantly, many of the genes that have been shown to be differentially expressed in other OA cell types/tissues, including ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) and prostaglandin E synthase (PTGES), were found to be expressed at significantly higher levels in OA meniscal cells. This consistency suggests that many of the genes detected in our study are disease-specific.ConclusionOur findings suggest that OA is a whole joint disease. Meniscal cells may play an active role in the development of OA. Investigation of the gene expression profiles of OA meniscal cells may reveal new therapeutic targets for OA therapy and also may uncover novel disease markers for early diagnosis of OA.

Active Surveillance of Very-low-risk Prostate Cancer in the Setting of Active Treatment of Benign Prostatic Hyperplasia With 5α-reductase Inhibitors

OBJECTIVE To review the efficacy of treating benign prostatic hyperplasia and very-low-risk prostate cancer (PCa) in patients receiving active surveillance and 5α-reductase inhibitor (5-ARI; finasteride or dutasteride) treatment. MATERIALS AND METHODS Eighty-two men with very-low-risk PCa (clinical stage T1c, Gleason score ≤ 6, <3 biopsy cores positive with ≤ 50% involvement, and prostate-specific antigen density ≤ 0.15 ng/mL/g) and benign prostatic hyperplasia (≥ 30 cm(3)) received active surveillance and were treated with a 5-ARI. RESULTS All 82 men completed 1 year of 5-ARI therapy (n = 79) or underwent early biopsy for cause (n = 3). Restaging biopsies were performed for 76 men (22 underwent a second restaging biopsy and 1 a third restaging biopsy), 4 patients were awaiting biopsy, and 2 were lost to follow-up before the first restaging biopsy. At the first restaging biopsy, of the 76 men, 41 (54%) had no PCa, 16 (21%) continued to have very-low-risk PCa, 15 (20%) had progressed to low-risk PCa (>2 cores positive and Gleason score ≤ 6), and 4 (5%) had progressed to intermediate-risk PCa (Gleason score 7). Of the 76 biopsies, 20 were performed early for cause, with 11 (55%) showing PCa progression. Of the 82 patients, 22 (27%) underwent treatment of PCa. CONCLUSION Active surveillance of very-low-risk PCa in the setting of 5-ARI therapy for benign prostatic hyperplasia appears to be a safe therapeutic option, because most (57 of 82; 70%) patients maintained very-low-risk PCa or had negative follow-up biopsies during a 3-year follow-up period. Complementary to the Prostate Cancer Prevention Trial, our results indicate that 5-ARI therapy increases prostate-specific antigen sensitivity and can aid the clinician in appropriately targeting biopsies.

Phosphocitrate is potentially a disease-modifying drug for noncrystal-associated osteoarthritis.

Phosphocitrate (PC), a calcification inhibitor, inhibits the development of crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the molecular mechanisms underlying its disease-modifying effect remain elusive. This study sought to test the hypothesis that PC has calcium crystal-independent biological activities which are, at least in part, responsible for its disease-modifying activity. We found that PC inhibited the proliferation of OA fibroblast-like synoviocytes in the absence of calcium crystals. Consistent with its effect on cell proliferation, PC downregulated the expression of numerous genes classified in cell proliferation. PC also downregulated the expression of many genes classified in angiogenesis and inflammatory response including prostaglandin-endoperoxide synthase 2, interleukin-1 receptor, type I, and chemokine (C-C motif) ligand 2. In contrast, PC upregulated the expression of many genes classified in musculoskeletal tissue development, including aggrecan, type I collagen, and insulin-like growth factor binding protein 5. These findings suggest that PC is not only a promising disease-modifying drug for crystal-associated OA but also for noncrystal-associated OA.

Ultrasound-guided oblique approach for peripheral venous access in a phantom model

BackgroundUltrasound (US) vascular guidance is traditionally performed in transverse (T) and longitudinal (L) axes, each with drawbacks. We hypothesized that the introduction of a novel oblique (O) approach would improve the success of US-guided peripheral venous access. We examined emergency physician (EP) performance using the O approach in a gel US phantom.MethodsIn a prospective, case control study, EPs were enrolled from four levels of physician experience including postgraduate years one to three (PGY1, PGY2, PGY3) and attending physicians. After a brief training session, each participant attempted vessel aspiration using a linear probe in T, L, and O axes on a gel US phantom. Time to aspiration and number of attempts to aspiration were recorded. The approach order was randomized, and descriptive statistics were used.ResultsTwenty-four physicians participated. The first-attempt success rate was lower for O, 45.83%, versus 70.83% for T (p = 0.03) and 83.33% for L (p = 0.01). The average time to aspiration was 12.5 s (O) compared with 9.47 s (T) and 9.74 s (L), respectively. There were no significant differences between all four groups in regard to total amount of time and number of aspiration attempts; however, a trend appeared revealing that PGY3 and attending physicians tended to aspirate in less time and by fewer attempts in all three orientations when compared with the PGY2 and PGY1 physicians.ConclusionIn this pilot study, US-guided simulated peripheral venous access using a phantom gel model in a mixed user group showed that the novel oblique approach was not initially more successful versus T and L techniques.