Outcomes of anatomic shoulder arthroplasty in primary osteoarthritis in type B glenoids.

BACKGROUND: Primary glenohumeral osteoarthritis with posterior wear of the glenoid and posterior subluxation of the humerus (Walch type B) presents a challenge to the treating surgeon. Our hypothesis was that glenoids with biconcavity (B2) would be associated with worse outcomes (functional scores and complications) than B1 glenoids. MATERIALS AND METHODS: We retrospectively analyzed prospectively collected data on 112 anatomic total shoulder arthroplasties (104 patients) with B glenoids. Preoperative computed tomography identified 64 B1 glenoids and 48 B2 glenoids (50 and 37 available for follow-up). RESULTS: A significant difference between B1 and B2 glenoids was noted in average retroversion (11° vs. 16°; P < .001) and average posterior humeral subluxation (65% vs. 75%; P < .001). No significant difference was seen in mean age (69.5 vs. 69.2 years) or body mass index (28.5 vs. 27.4) at time of surgery. At average follow-up of 60 months (range, 23-120 months), glenoid component radiolucencies (51.6%, B1; 47.9%, B2), range of motion, preoperative and postoperative scores of the shortened Disabilities of the Arm, Shoulder, and Hand questionnaire, and patient satisfaction were not significantly different between the 2 groups. Four revisions (4.6%) were documented for acute postoperative infection (2.3%), subscapularis failure (1.1%), and glenoid loosening (1.1%). CONCLUSIONS: Although biconcave glenoids commonly have more severe retroversion and posterior subluxation of the humerus, we were unable to find a clinical or radiographic difference in outcome of patients with B1 or B2 glenoids treated with anatomic total shoulder arthroplasty at intermediate-term follow-up. Continued clinical and radiographic follow-up of these cohorts will be necessary to assess any future divergence in outcome.

Intertrochanteric hip fractures treated with the trochanteric fixation nail and sliding hip screw.

The primary treatment options for intertrochanteric hip fractures are a sliding hip screw (SHS) and an intramedullary device, with each having its own advantages and disadvantages. The authors retrospectively compared all intertrochanteric hip fractures between 2003 and 2005 using a cephalomedullary nail--the trochanteric fixation nail (TFN)--to those using a SHS. Outcome measures included the following parameters: age, gender, fracture classification, operation time, blood loss, transfusions, complications, follow-up, length of stay, and hospital cost. A total of 95 patients were included in the study (51 SHS and 44 TFN). The two groups were similar in age (p = .52), blood loss (p = .20), follow-up (p = .13), length of stay (p = .63), and hospital costs (p = .70). The TFN procedure required shorter operative times (56.5 min, p < .004) and was used in more complex fracture patterns (p < .03). The SHS group had fewer blood transfusions (1.2 units, p < .0008). The SHS group had a higher complication rate of 19.6%, versus the TFN group's 11.4% rate (p = .13). The TFN is an appropriate and acceptable treatment method for intertrochanteric hip fractures.

Comparing pain reduction following kyphoplasty and vertebroplasty for osteoporotic vertebral compression fractures.

BACKGROUND: Osteoporosis with subsequent osteoporotic vertebral compression fractures is an increasingly important disease due not only to its significant economic impact but also to the increasing age of our population. Pain reduction and stabilization are of primary importance with osteoporotic vertebral compression fractures. Although many patients heal with conservative treatment consisting of rest or activity modification, analgesics, and bracing, the management of severe pain compels some patients to seek surgical intervention via 2 procedures: vertebroplasty and kyphoplasty. Although there is abundant support in the literature for both procedures, there remains debate over which procedure can most successfully reduce patients' perception of pain. OBJECTIVE: To determine the amount of pain reduction using the visual analog scale (VAS) with kyphoplasty and vertebroplasty in the treatment of osteoporotic vertebral compression fractures. DESIGN: Meta-analysis METHODS: A systematic review and meta-analysis of the available literature was performed to quantify the amount of pain reduction using the visual analog scale (VAS) between vertebroplasty and kyphoplasty for osteoporotic vertebral compression fractures. RESULTS: Twenty-one studies, 14 vertebroplasty and 7 kyphoplasty, qualified for inclusion representing totals of 1,046 vertebroplasty and 263 kyphoplasty patients treated, respectively. Kyphoplasty and vertebroplasty resulted in a more than 5 point drop in the VAS in the immediate postoperative period (p<0.00001). Between the two, the difference in early pain relief was not significant. At final follow-up, the long-term VAS was improved for both procedures, but the final follow-up VAS for vertebroplasty and kyphoplasty was not significant when compared to the initial postoperative VAS (p=0.25, p=0.38, respectively). CONCLUSIONS: The analysis demonstrates that both procedures reduce the amount of pain in the immediate postoperative period by approximately 50%. Both procedures reduce pain in symptomatic osteoporotic vertebral compression fractures that have failed conservative treatment. Randomized controlled trials are needed to provide definitive data on which procedure is the most effective for vertebral compression fractures.

Toward a More Robust Prediction of Pulmonary Embolism in Trauma Patients: A Risk Assessment Model Based on 38,000 Patients.

OBJECTIVES: Pulmonary embolism (PE) is a rare but sometimes fatal complication of trauma. Risk stratification models identify patients at increased risk of PE; however, they are often complex and difficult to use. This research aims to develop a model, based on a large sample of trauma patients, which can be easily and quickly used at the time of admission to predict PE. METHODS: This study used trauma registry data from 38,597 trauma patients. Of these, 239 (0.619%) developed a PE. We targeted demographic and injury data, prehospital information, and data on treatments and events during hospitalization. A multivariate binary logistic regression model was developed to predict the odds of developing a PE during hospitalization. The model was developed using a 50% randomly selected development subsample and then tested for accuracy using the remaining 50% validation sample. RESULTS: We found 7 statistically significant predictors of PE, including (1) age [odds ratio (OR) = 1.01; 95% CI, 1.00-1.02; P = 0.05], (2) obesity (OR = 2.54; 95% CI, 1.29-4.99; P < 0.01), (3) injury from motorcycle accident (OR = 2.01; 95% CI, 1.25-3.22; P < 0.01), (4) arrival by helicopter (OR = 2.91; 95% CI, 1.16-7.27; P = 0.02), (5) emergency department admission pulse rate (OR = 1.01; 95% CI, 1.0-1.02; P = 0.06), (6) admission to intensive care unit (OR = 5.03; 95% CI, 3.12-8.12; P < 0.01), and (7) injury location, including thorax (OR = 1.57; 95% CI, 1.04-2.37; P = 0.03), abdomen (OR = 1.56; 95% CI, 1.04-2.33; P = 0.03), and lower extremity injuries (OR = 2.85; 95% CI, 3.12-8.12; P < 0.01). Our model was able to discriminate between predicted and actual PE events with a receiver operating characteristic area under the curve of 0.87. By identifying the top 25% high-risk patients, we were able to predict 80%-84% of pulmonary emboli. CONCLUSIONS: This knowledge allows us to focus stronger thromboprophylactic efforts on patients at highest risk. This model can be used to rapidly identify trauma patients at high risk for PE. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Hip arthroscopy: a report on a cohort of orthopaedic surgeons.

Successful hip arthroscopy depends on proper patient selection and reasonable patient expectations. The purpose of this study is to report the results of hip arthroscopy in orthopaedic surgeons who represent the most informed cohort. This report is based on a retrospective review of prospectively collected data among 24 orthopaedic surgeons (1 bilateral). Follow-up averaged 48 months (range 12-120 months). They were all males with an average age of 45 years (range 30-64 years). All improved with an average of 18 points (preoperative 75; post-operative 93); although one underwent repeat arthroscopy and one was converted to total hip arthroplasty at 54 months. There were numerous diagnoses and procedures performed and one complication (acute coronary artery occlusion). They resumed seeing patients at an average of 1.6 weeks (range 2 days-4 weeks) and operating at an average of 3.1 weeks (range 6 days-8 weeks). This report spans three decades, thus representing a heterogeneous population in terms of diagnoses and treatment. Nonetheless, successful results are noted. As a cohort, orthopaedic surgeons possess the greatest insight into hip arthroscopy, but as patients, often they must modulate their expectations in order to match the understanding of the realities of the procedure.

Treating neurodegenerative conditions through the understanding of neuronal apoptosis.

Neurological diseases disrupt the quality of the lives of patients and often leads to their premature deaths. A common feature of most neurological diseases is the degeneration of neurons. It is generally accepted that neuronal loss, in these diseases, occurs by the inappropriate activation of a cell-suicide process called apoptosis. Drugs that inhibit neuronal apoptosis could thus be candidates for therapeutic intervention in neurodegenerative disorders. In this review we describe advances made in recent years on the molecules and signal transduction pathways that regulate neuronal apoptosis either positively or negatively. Emphasis is on molecules that are being targeted for the potential treatment of neurodegenerative conditions in humans. Furthermore, we will summarize results from studies performed using small-molecule neuroprotective drugs that target specific signaling molecules known to regulate neuronal apoptosis.

Brain chemotherapy from the bench to the clinic: targeting neuronal survival with small molecule inhibitors of apoptosis.

Increasing evidence implicates aberrant apoptosis as a fundamental cause of neurodegenerative diseases. Thus elucidating the underlying causes of neuronal programmed cell death may foster the development of therapeutic interventions. Research in the last 15 years provided a solid foundation for understanding molecular mechanisms of neuronal apoptosis. This review discusses the major molecules and signaling pathways leading to neuronal survival or apoptosis with emphasis on several small molecule inhibitors that target neuronal survival with the hope of impeding the detrimental effects of neurodegenerative diseases.

Inhibition of GSK3beta is a common event in neuroprotection by different survival factors.

Depolarizing concentrations of potassium (HK, 25 mM), cyclic AMP elevating agents and analogs (cAMP), insulin-like growth factor-1 (IGF-1), or lithium can maintain the survival of cultured rat cerebellar granule neurons (CGNs). We investigated the possibility that the signal transduction pathways utilized by these four survival factors converge in regulating a common molecular target. We targeted the regulation of the kinase GSK3beta as the critical event in the survival directed by the four survival factors. We found that treatment of CGNs with HK, the cAMP-elevating agent forskolin, IGF-1, and lithium resulted in phosphorylation of GSK3beta at serine-9 and thus its inactivation. Furthermore, pharmacological inhibition of core components in the survival signaling cascades initiated by HK, forskolin, IGF-1, and lithium causes apoptosis and activation of GSK3beta accompanies this death. Finally, we examined the pharmacological inhibitors of GSK3beta, GSK3 inhibitor I, TDZD-8, and SB-415286, for their ability to prevent low potassium (LK)-induced apoptosis. Although previous reports demonstrate inhibition of GSK3beta in in vitro kinase assays with GSK3 inhibitor I and TDZD-8, we were unable to detect inhibition of GSK3beta in neuronal cultures treated with these compounds and thus no protection from LK-induced apoptosis. SB-415286 on the other hand, was able to rescue CGNs from cell death. Taken together, we conclude that regulation of GSK3beta is a critical convergence event in the promotion of CGN survival by different factors.

Survival of cultured cerebellar granule neurons can be maintained by Akt-dependent and Akt-independent signaling pathways.

Cerebellar granule neurons can be maintained in culture by four factors: depolarizing levels of potassium (HK, 25 mM), cyclic AMP elevating agents and analogs (cyclic adenosine monophosphate, cAMP), insulin-like growth factor-1 (IGF-1), or lithium. We investigated the possibility that the signal transduction pathways utilized by these four survival factors might converge at a common molecular target and that the serine/threonine kinase Akt might be the convergent molecule. Previous research demonstrated that the four factors could phosphorylate and activate Akt; thus, using pharmacological inhibition of Akt and overexpression of an adenoviral delivered dominant negative Akt construct, we analyzed the role of Akt in the survival mediated by each factor. We found that although Akt is required for the survival mediated by IGF-1 and lithium, it is dispensable for the survival mediated by high potassium and cAMP.

Inhibition of neuronal apoptosis by the cyclin-dependent kinase inhibitor GW8510: identification of 3' substituted indolones as a scaffold for the development of neuroprotective drugs.

Increasing evidence suggests that neuronal apoptosis is triggered by the inappropriate activation of cyclin-dependent kinases leading to an abortive re-entry of neurons into the cell cycle. Pharmacological inhibitors of cell-cycle progression may therefore have value in the treatment of neurodegenerative diseases in humans. GW8510 is a 3' substituted indolone that was developed recently as an inhibitor of cyclin-dependent kinase 2 (CDK2). We found that GW8510 inhibits the death of cerebellar granule neurons caused by switching them from high potassium (HK) medium to low potassium (LK) medium. Although GW8510 inhibits CDK2 and other CDKs when tested in in vitro biochemical assays, when used on cultured neurons it only inhibits CDK5, a cytoplasmic CDK that is not associated with cell-cycle progression. Treatment of cultured HEK293T cells with GW8510 does not inhibit cell-cycle progression, consistent with its inability to inhibit mitotic CDKs in intact cells. Neuroprotection by GW8510 is independent of Akt and MEK-ERK signaling. Furthermore, GW8510 does not block the LK-induced activation of Gsk3beta and, while inhibiting c-jun phosphorylation, does not inhibit the increase in c-jun expression observed in apoptotic neurons. We also examined the effectiveness of other 3' substituted indolone compounds to protect against neuronal apoptosis. We found that like GW8510, the VEGF Receptor 2 Kinase Inhibitors [3-(1H-pyrrol-2-ylmethylene)-1,3-dihydroindol-2-one], {(Z)-3-[2,4-Dimethyl-3-(ethoxycarbonyl)pyrrol-5-yl)methylidenyl]indol-2-one} and [(Z)-5-Bromo-3-(4,5,6,6-tetrahydro-1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one], the Src family kinase inhibitor SU6656 and a commercially available inactive structural analog of an RNA-dependent protein kinase inhibitor 5-Chloro-3-(3,5-dichloro-4-hydroxybenzylidene)-1,3-dihydro-indol-2-one, are all neuroprotective when tested on LK-treated neurons. Along with our recent identification of the c-Raf inhibitor GW5074 (also a 3' substituted indolone) as a neuroprotective compound, our findings identify the 3' substituted indolone as a core structure for the designing of neuroprotective drugs that may be used to treat neurodegenerative diseases in humans.

Akt is a downstream target of NF-kappa B.

The ubiquitously expressed transcription factor NF-kappa B and the serine-threonine kinase Akt both are involved in the promotion of cell survival. Although initially believed to operate as components of distinct signaling pathways, several studies have demonstrated that the NF-kappa B and Akt signaling pathways can converge. Indeed, I kappa B kinase, the kinase involved in NF-kappa B activation, is a substrate of Akt, and activation of Akt therefore stimulates NF-kappa B activity. Although these results place Akt upstream of NF-kappa B activation in the sequence of signaling events, we report that this may not necessarily be the case and that Akt is a downstream target of NF-kappa B. Treatment of NIH3T3 cells with the NF-kappa B activators, tumor necrosis factor (TNF) alpha and lipopolysaccharide, results in the stimulation of Akt phosphorylation. The stimulation of Akt is, however, detected only after I kappa B-alpha degradation is induced by these agents. The nuclear translocation of p65 and increased DNA binding activity of NF-kappa B also precede Akt phosphorylation. Treatment with two pharmacological inhibitors of NF-kappa B, SN50 and N-tosyl-l-phenylalanine chloromethyl ketone (TPCK), blocks TNF-induced Akt activation. On the other hand TNF-mediated NF-kappa B activation is not reduced by the phosphoinositide-3 kinase inhibitors wortmannin and LY294002, although these inhibitors completely block the activation of Akt. These results suggest that NF-kappa B is required for TNF-mediated Akt activation and that it lies upstream of the stimulation of Akt. Consistent with this conclusion is the finding that overexpression of p65/RelA leads to Akt phosphorylation in the absence of extracellular stimulatory factors, whereas overexpression of I kappa B-alpha reduces Akt phosphorylation below basal levels. Interestingly, in addition to stimulating the phosphorylation of Akt, overexpression of p65 causes an increase in the expression of Akt mRNA and protein.

The c-Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK-ERK and Akt-independent mechanism.

Cerebellar granule neurons undergo apoptosis when switched from a medium containing high potassium (HK) to one that has low potassium (LK). LK-induced cell death is blocked by GW5074 [5-Iodo-3-[(3,5-dibromo-4-hydroxyphenyl) methylene]-2-indolinone], a synthetic drug that inhibits c-Raf activity in vitro. GW5074 has no direct effect on the activities of several apoptosis-associated kinases when assayed in vitro. In contrast to its effect in vitro, treatment of neurons with GW5074 causes c-Raf activation (when measured in vitro in the absence of the drug) and stimulates the Raf-MEK-ERK pathway. Treatment of neurons with GW5074 also leads to an increase in the activity of B-Raf, which is not inhibited by GW5074 in vitro at concentrations at which the drug exerts its neuroprotective effect. PD98059 and U0126, two distinct inhibitors of MEK, block the activation of ERK by GW5074 but have no effect on its ability to prevent cell death. Overexpression of a dominant-negative form of Akt does not reduce the efficacy of GW5074, demonstrating an Akt-independent mechanism of action. Neuroprotection is inhibited by SN-50, a specific inhibitor of nuclear factor-kappa B (NF-kappaB) and by the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) implicating NF-kappaB and Ras in the neuroprotective signaling pathway activated by GW5074. In addition to preventing LK-induced apoptosis, treatment with GW5074 protects against the neurotoxic effects of MPP+ and methylmercury in cerebellar granule neurons, and glutathione depletion-induced oxidative stress in cortical neurons. Furthermore, GW5074 prevents neurodegeneration and improves behavioral outcome in an animal model of Huntington's disease. Given its neuroprotective effect on distinct types of cultured neurons, in response to different neurotoxic stimuli, and in an animal model of neurodegeneration, GW5074 could have therapeutic value against neurodegenerative pathologies in humans.