Sacral insufficiency fractures: an easily overlooked cause of back pain in the ED.

Sacral insufficiency fractures are an important and treatable cause of severe back pain. Despite publication of several case reports since its original description in 1982, awareness of these injuries remains inadequate in emergency medicine. Most patients are elderly women presenting with intractable lower back pain. Postmenopausal osteoporosis is the most significant risk factor. Marked sacral tenderness is common. Neurologic impairment is rarely detectable. Routine radiography of the spine and pelvis is usually inconclusive. Computed tomography remains the diagnostic modality of choice. Treatment is usually conservative.

Osteonecrosis following alcohol, cocaine, and steroid use.

Alcohol, steroids and cocaine have all been shown to be independent risk factors for osteonecrosis when taken in excess. Here we present a case of a young girl who developed debilitating osteonecrosis secondary to low doses of alcohol, steroids and cocaine. We feel it is important to highlight to those caring for such patients of the potential devastating complication of these three agents.

Parotid lymphomas--clinical and computed tomographic imaging features.

OBJECTIVE: To review the clinical presentation and computed tomography (CT) imaging characteristics of all parotid lymphomas diagnosed at the study institution over a 7-year period. DESIGN: Retrospective chart review of parotid lymphomas diagnosed between 1997 and 2004. SUBJECTS: A total of 121 patients with parotid lesions were identified. After retrospective chart review, a total of 10 patients with histologically proven parotid lymphoma were included in the study, 8 of whom had CT scans available for assessment. RESULTS: Ten patients with histologically proven lymphoma of the parotid gland were identified from among 121 patients with parotid neoplasms, an incidence in this series of 8.3%. All lymphomas were of non-Hodgkin's type. All patients presented with a painless unilateral parotid swelling. Most patients had a short history of less than 4 months' duration, of whom 3 presented with a rapidly evolving swelling of less then 1 month's duration. No patient had a background of Sjögren's disease or any other autoimmune disorders. The commonest finding noted on CT was of a unilateral, single mass of relative soft-tissue homogeneity with poorly defined, indistinct tumour margins. Associated loco-regional lymphadenopathy was identified in 2 cases, 1 clinically and another radiologically; multiple ipsilateral lesions were noted in 2 cases. No cases of contralateral disease were observed. CONCLUSION: Lymphoma has a clinical presentation similar to other neoplasms arising within the parotid gland. A unilateral, non-tender swelling was a universal finding. A history of less than 4 months may suggest the possibility of lymphoma. CT scanning is a useful adjunctive investigation to determine the site and extent of the disease, loco-regional nodal status and contralateral gland and neck status. Multifocality and associated adenopathy are associated with, but not exclusive to, parotid lymphoma. Although poor tumour boundary definition on CT imaging is a strong predictor of malignancy, no pathognomonic finding specific for lymphoma has been identified. The potential diagnosis of parotid lymphoma should be considered in all patients who present with a parotid mass.

Azepanone-based inhibitors of human cathepsin L.

The extension of a previously reported cathepsin K azepanone-based inhibitor template to the design and synthesis of potent and selective inhibitors of the homologous cysteine protease cathepsin L is detailed. Structure-activity studies examining the effect of inhibitor selectivity as a function of the P3 and P2 binding elements of the potent cathepsin K inhibitor 1 revealed that incorporation of either a P3 quinoline-8-carboxamide or a naphthylene-1-carboxamide led to increased selectivity for cathepsin L over cathepsin K. Substitution of the P2 leucine of 1 with either a phenylalanine or a beta-naphthylalanine also resulted in an increased selectivity for cathepsin L over cathepsin K. Molecular modeling studies with the inhibitors docked within the active sites of both cathepsins L and K have rationalized the observed selectivities. Optimization of cathepsin L binding by the combination of the P3 naphthylene-1-carboxamide with the P2 beta-naphthylalanine provided 15, which is a potent, selective, and competitive inhibitor of human cathepsin L with a K(i) = 0.43 nM.

What next for rheumatoid arthritis therapy?

Introduction of biological agents for the treatment of the chronic inflammatory joint disease rheumatoid arthritis has reinvigorated research into this debilitating disease. These agents have been shown to both act on the signs and symptoms of disease, as well as retard the progression of joint destruction. However, these agents are not efficacious in all cases and their expense and route of administration can severely limit their use. Therefore the search continues not only for additional targets to help those individuals refractive to current therapy but also for more affordable orally active small molecule alternatives to biological agents.

Small-molecule inhibitors of NF-kappaB for the treatment of inflammatory joint disease.

Recent advances in our understanding of the role of cytokine networks in inflammatory processes have led to the development of novel biological agents for the treatment of chronic inflammatory diseases. At the present time, significant efforts are focused on characterizing the complex signal transduction cascades that are activated by these cytokines and, in turn, regulate their expression. The transcription factor NF-kappaB is a pivotal regulator of the inducible expression of key proinflammatory mediators, and activated NF-kappaB has been observed in several debilitating inflammatory disorders, including rheumatoid arthritis and osteoarthritis. In light of its central role in inflammation, the identification of inhibitors of NF-kappaB should provide novel therapeutics for the treatment of chronic joint disease.

Extranodal lymphoma: clinical presentation and diagnostic pitfalls.

Non-Hodgkin's lymphomas (NHL) are known to present extranodally in 25% of cases, in contrast to Hodgkin's disease which rarely involves extranodal sites. In this article, the authors will to review the presentation of extranodal head and neck NHL and the difficulties that can be encountered in making the diagnosis in these cases.

Let's talk about sex: gender norms and sexual health in English schools.

The sexual health of young people in England is an urgent public health concern. While interventions to address young people's sexual health have focussed on knowledge, skills and contraception access, amazingly none in the UK has explicitly addressed the effects of the social hierarchies of gender and gendered behavioural ideals that shape young people's sexual expectations, attitudes and behaviour. The lack of attention to gender is a persistent gap in health research, practice and policy. A rigorous evaluation of such an intervention package would go some way to building an evidence base for challenging gender norms, which appear to be strongly associated with adverse sexual health outcomes.

Outcome analysis of patients with acute pancreatitis by using an artificial neural network.

RATIONALE AND OBJECTIVES: The authors performed this study to evaluate the ability of an artificial neural network (ANN) that uses radiologic and laboratory data to predict the outcome in patients with acute pancreatitis. MATERIALS AND METHODS: An ANN was constructed with data from 92 patients with acute pancreatitis who underwent computed tomography (CT). Input nodes included clinical, laboratory, and CT data. The ANN was trained and tested by using a round-robin technique, and the performance of the ANN was compared with that of linear discriminant analysis and Ranson and Balthazar grading systems by using receiver operating characteristic analysis. The length of hospital stay was used as an outcome measure. RESULTS: Hospital stay ranged from 0 to 45 days, with a mean of 8.4 days. The hospital stay was shorter than the mean for 62 patients and longer than the mean for 30. The 23 input features were reduced by using stepwise linear discriminant analysis, and an ANN was developed with the six most statistically significant parameters (blood pressure, extent of inflammation, fluid aspiration, serum creatinine level, serum calcium level, and the presence of concurrent severe illness). With these features, the ANN successfully predicted whether the patient would exceed the mean length of stay (Az = 0.83 +/- 0.05). Although the Az performance of the ANN was statistically significantly better than that of the Ranson (Az = 0.68 +/- 0.06, P < .02) and Balthazar (Az = 0.62 +/- 0.06, P < .003) grades, it was not significantly better than that of linear discriminant analysis (Az = 0.82 +/- 0.05, P = .53). CONCLUSION: An ANN may be useful for predicting outcome in patients with acute pancreatitis.

Mechanical injury potentiates proteoglycan catabolism induced by interleukin-6 with soluble interleukin-6 receptor and tumor necrosis factor alpha in immature bovine and adult human articular cartilage.

OBJECTIVE: Traumatic joint injury can damage cartilage and release inflammatory cytokines from adjacent joint tissue. The present study was undertaken to study the combined effects of compression injury, tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6) and its soluble receptor (sIL-6R) on immature bovine and adult human knee and ankle cartilage, using an in vitro model, and to test the hypothesis that endogenous IL-6 plays a role in proteoglycan loss caused by a combination of injury and TNFalpha. METHODS: Injured or uninjured cartilage disks were incubated with or without TNFalpha and/or IL-6/sIL-6R. Additional samples were preincubated with an IL-6-blocking antibody Fab fragment and subjected to injury and TNFalpha treatment. Treatment effects were assessed by histologic analysis, measurement of glycosaminoglycan (GAG) loss, Western blot to determine proteoglycan degradation, zymography, radiolabeling to determine chondrocyte biosynthesis, and Western blot and enzyme-linked immunosorbent assay to determine chondrocyte production of IL-6. RESULTS: In bovine cartilage samples, injury combined with TNFalpha and IL-6/sIL-6R exposure caused the most severe GAG loss. Findings in human knee and ankle cartilage were strikingly similar to those in bovine samples, although in human ankle tissue, the GAG loss was less severe than that observed in human knee tissue. Without exogenous IL-6/sIL-6R, injury plus TNFalpha exposure up-regulated chondrocyte production of IL-6, but incubation with the IL-6-blocking Fab significantly reduced proteoglycan degradation. CONCLUSION: Our findings indicate that mechanical injury potentiates the catabolic effects of TNFalpha and IL-6/sIL-6R in causing proteoglycan degradation in human and bovine cartilage. The temporal and spatial evolution of degradation suggests the importance of transport of biomolecules, which may be altered by overload injury. The catabolic effects of injury plus TNFalpha appeared partly due to endogenous IL-6, since GAG loss was partially abrogated by an IL-6-blocking Fab.

Human articular chondrocytes produce IL-7 and respond to IL-7 with increased production of matrix metalloproteinase-13.

INTRODUCTION: Fibronectin fragments have been found in the articular cartilage and synovial fluid of patients with osteoarthritis and rheumatoid arthritis. These matrix fragments can stimulate production of multiple mediators of matrix destruction, including various cytokines and metalloproteinases. The purpose of this study was to discover novel mediators of cartilage destruction using fibronectin fragments as a stimulus. METHODS: Human articular cartilage was obtained from tissue donors and from osteoarthritic cartilage removed at the time of knee replacement surgery. Enzymatically isolated chondrocytes in serum-free cultures were stimulated overnight with the 110 kDa alpha5beta1 integrin-binding fibronectin fragment or with IL-1, IL-6, or IL-7. Cytokines and matrix metalloproteinases released into the media were detected using antibody arrays and quantified by ELISA. IL-7 receptor expression was evaluated by flow cytometry, immunocytochemical staining, and PCR. RESULTS: IL-7 was found to be produced by chondrocytes treated with fibronectin fragments. Compared with cells isolated from normal young adult human articular cartilage, increased IL-7 production was noted in cells isolated from older adult tissue donors and from osteoarthritic cartilage. Chondrocyte IL-7 production was also stimulated by combined treatment with the catabolic cytokines IL-1 and IL-6. Chondrocytes were found to express IL-7 receptors and to respond to IL-7 stimulation with increased production of matrix metalloproteinase-13 and with proteoglycan release from cartilage explants. CONCLUSION: These novel findings indicate that IL-7 may contribute to cartilage destruction in joint diseases, including osteoarthritis.

Proteoglycan degradation after injurious compression of bovine and human articular cartilage in vitro: interaction with exogenous cytokines.

OBJECTIVE: Traumatic joint injury leads to an increased risk of osteoarthritis (OA), but the progression to OA is not well understood. We undertook this study to measure aspects of proteoglycan (PG) degradation after in vitro injurious mechanical compression, including up-regulation of enzymatic degradative expression and cytokine-stimulated degradation. METHODS: Articular cartilage tissue explants were obtained from newborn bovine femoropatellar groove and from adult normal human donor knee and ankle tissue. Following injurious compression of the cartilage, matrix metalloproteinase 3 (MMP-3) and MMP-13 messenger RNA (mRNA) expression levels were measured by Northern analysis, and PG loss to the medium after cartilage injury was measured in the presence and absence of added exogenous cytokine (interleukin-1alpha [IL-1alpha] or tumor necrosis factor alpha [TNFalpha]). RESULTS: During the first 24 hours after injury in bovine cartilage, MMP-3 mRNA levels increased 10-fold over the levels in control cartilage (n = 3 experiments), whereas MMP-13 mRNA levels were unchanged. PG loss was significantly increased after injury, but only by 2% of the total PG content and only for the first 3 days following injury. However, compared with injury alone or cytokine treatment alone, treatment of injured tissue with either 1 ng/ml IL-1alpha or 100 ng/ml TNFalpha caused marked increases in PG loss (35% and 54%, respectively, of the total cartilage PG content). These interactions between cytokine treatment and injury were statistically significant. In human knee cartilage, the interaction was also significant for both IL-1alpha and TNFalpha, although the magnitude of increase in PG loss was lower than that in bovine cartilage. In contrast, in human ankle cartilage, there was no significant interaction between injury and IL-1alpha. CONCLUSION: The cytokines IL-1alpha and TNFalpha can cause a synergistic loss of PG from mechanically injured bovine and human cartilage. By attempting to incorporate interactions with other joint tissues that may be sources of cytokines, in vitro models of mechanical cartilage injury may explain aspects of the interactions between mechanical forces and degradative pathways which lead to OA progression.