The role of relaxin in anterior cruciate ligament injuries: a systematic review.

OBJECTIVE: Anterior cruciate ligament (ACL) tears are exceedingly common among the athletic population and are seen with higher incidence in females. Observational studies have noted peak ACL tear rates in the luteal phase of the menstrual cycle, a time in which the hormone relaxin peaks in serum concentration. METHODS: A systematic review of the literature was performed. Inclusion criteria specified all prospective and retrospective studies which included the role of relaxin in the pathogenesis of ACL tears. RESULTS: Six studies met inclusion criteria yielding 189 subjects from clinical studies and 51 in vitro samples. Included studies found that ACL samples exhibit selective relaxin binding. When pre-treated with estrogen prior to relaxin exposure, female ACL tissue samples exhibit increased expression of collagen degrading receptors. CONCLUSION: Relaxin displays binding specificity to the female ACL and increased serum concentrations are correlated with increased ACL tear rates in female athletes. Further research is needed in this area. LEVEL OF EVIDENCE: V.

Surgical Treatment of Shoulder Infection Following Rotator Cuff Repair.

Background: Deep infection after rotator cuff repair (RCR) can cause significant morbidity and healthcare burden. Outcomes of surgical treatment of infection following RCR are limited. This study aimed to assess the clinical course and outcomes related to surgical management of deep infection following RCR. Methods: Patients treated with debridement for infection after RCR at a single institution were included. Postoperative deep infection included the following criteria: persistent drainage more than five days from index surgery, development of a sinus tract to the joint, ≥ 2 positive cultures at the time of revision surgery with the same bacteria, or presence of purulence. Functional outcomes (ASES, SANE, SF-12) were assessed at a minimum of 1-year post-debridement. Results: Twenty-three patients were included and analyzed at mean six years post-debridement. All were free of infection at the final follow-up. The average age was 55 years; fifteen (65.2%) had infection after primary RCR and eight (34.8%) after revision RCR. Twelve (52.2%) patients required a repeat debridement prior to eradicating infection for an average of 1.9 surgeries before clearance of infection. Statistically significant predictors of need for a repeat debridement included initial open RCR (P = .02), open debridement (P = .002) and infection requiring IV antibiotics (P = .014). Postoperative ASES, SANE, SF-12M, SF-12P, and satisfaction scores were 71.7±25.7, 67.0±28.1, 55.5±6.5, 38.4±14.3 and 3.7±1.3, respectively. Conclusion: Deep infection after RCR can be treated with open or arthroscopic debridement. However, more than 50% of patients may require multiple debridements. Final functional results after infection control following RCR are satisfactory. However, chronic infection predicts worse functional outcomes.

Fixed- vs. variable-angle humeral neck cut in anatomic total shoulder arthroplasty: a randomized controlled trial.

BACKGROUND: Variable neck-shaft angle (NSA) stemmed humeral components have been incorporated into certain implant designs to better re-create normal anatomy in total shoulder arthroplasty (TSA). The purpose of this study was to determine if premorbid glenohumeral joint anatomy is better restored with a fixed- vs. variable-NSA prosthesis. METHODS: A randomized controlled trial was performed including 50 patients with osteoarthritis indicated for primary anatomic TSA. Patients were randomized preoperatively to receive either a variable- (n = 26) or fixed-NSA (n = 24) prosthesis. Humeral neck cut in the variable-NSA group matched the patient's anatomic neck, with prosthetic NSA of 127.5°, 132.5°, and 137.5° available. Fixed-NSA cuts were made with an intramedullary guide of 132.5°. Preoperative and postoperative radiographs were evaluated for specific radiographic anatomic variables: NSA, head thickness, tuberosity-to-head height, head offset, articular arc, greater tuberosity offset, and center of rotation (COR). Postoperative radiographic criteria were compared between groups. RESULTS: No differences were found between groups in demographics or preoperative radiographic measures. When comparing average difference in preoperative and postoperative measurements in the fixed-NSA group, the humeral head offset from the humeral shaft axis significantly decreased by 1.4 mm (P = .046), and the COR moved superiorly (3.0 mm, P = .002) without significant medialization or lateralization. In the variable angle group, humeral head offset decreased but did not reach significance (1.2 mm, P = .091), and the COR also moved superiorly (2.9 mm, P < .001) without significant medialization or lateralization. All remaining radiographic parameters did not significantly change from pre- to postoperative imaging. In comparing the fixed- and variable-NSA groups' net change from the premorbid measurements, no significant differences were found in tuberosity-to-head height, head offset, or COR position in both the horizontal and vertical planes. CONCLUSIONS: Both fixed- and variable-NSA anatomic TSA humeral components demonstrate adequate restoration of premorbid anatomy radiographically.

Surgical anatomy of the axillary artery: clinical implications for open shoulder surgery.

BACKGROUND: Axillary artery injury is a devastating complication related to anterior shoulder surgery and can result in significant morbidity and/or mortality. The purpose of our study was to evaluate the course of the axillary artery in relation to bony landmarks of the shoulder and identify variations in artery position with humeral external rotation. MATERIALS AND METHODS: Dissection of 18 shoulders (9 fresh whole-body cadavers) with simulated vessel perfusion using radiopaque dye was performed. The axillary artery position was measured from multiple points including 2 points on the coracoid base (C1 and C2), 3 points on the coracoid tip (C3-C5), 4 points on the glenoid: superior, middle, and inferior glenoid (D1-D4), and 2 points on the lesser tuberosity (L1 and L2). Fluoroscopic measurements were taken and compared at 0° and 90° of external rotation (F1 vs. F1' and F2 vs. F2'). Manual and fluoroscopic measurements were compared with one another using Kendall's τb correlation. RESULTS: There were 6 male and 3 female cadavers with an average age of 67.2 ± 9.3 years (range: 49-77 years). The mean distance from the axillary artery to the coracoid base (C1 and C2) measured 21.1 ± 7.3 and 22.3 ± 7.4 mm, respectively, whereas the mean distance to the coracoid tip (C3, C4, and C5) measured 30.7 ± 9.3, 52.1 ± 20.2, and 46.5 ± 14.3 mm, respectively. Measurements relative to the glenoid face (D1, D2, and D3) showed a progressive decrease in mean distance from superior to inferior, measuring 31.6 ± 10.3, 16.5 ± 7.5, and 10.3 ± 7.3 mm, respectively, whereas D4 (inferior glenoid to axillary artery) measured 17.8 ± 10.7 mm. The minimum distance from the axillary artery to any point on the glenoid was as close as 4.1 mm (D3). There was a statistically significant difference in F1 (0° external rotation) vs. F1' (90° external rotation) (18.5 vs. 13.4 mm, P = .03). Kendall's τb correlation showed a strong, positive correlation between manual and fluoroscopic measurements (D4: 16.0 ± 12.5 mm vs. F1: 18.5 ± 10.7 mm) (τb = 0.556, P = .037). CONCLUSION: The axillary artery travels an average of 1-1.8 cm from the inferior glenoid margin, which puts the artery at significant risk. In addition, the artery is significantly closer to the inferior glenoid with humeral external rotation. Surgeons performing anterior shoulder surgery should have a thorough understanding of the axillary artery course and understand changes in the position of the artery with external rotation of the humerus.

Techniques for lower trapezius tendon transfer for the management of irreparable posterosuperior rotator cuff tears.

Irreparable posterosuperior rotator cuff tears are a challenging treatment problem. Several tendon transfers have been described for the treatment of irreparable tears. Recently the lower trapezius (LT) tendon transfer has grown in popularity. This procedure has shown promise in biomechanical studies, improving the external rotation moment arm at the side. This transfer may be done in several ways, including an open approach with an acromial osteotomy, mini-open, and arthroscopic-assisted. The purpose of this paper is to review the current evidence and rationale for the use of the LT transfer and to describe the available techniques.

Midterm outcomes of arthroscopic rotator cuff repair in patients aged 75 years and older.

BACKGROUND: Full-thickness rotator cuff tears remain a significant cause of pain and dysfunction in the elderly. Substantial improvement in pain and functional outcomes with arthroscopic cuff repair is possible. Recent data has shown that patients older than 70-75 years still have clinical improvement with operative rotator cuff repair. MATERIALS AND METHODS: This is a retrospective study of patients aged ≥75 years undergoing arthroscopic rotator cuff repair at a minimum of 24 months after surgery. Outcome measurements included range of motion (ROM), visual analog scale (VAS) pain scores, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores, Single Assessment Numeric Evaluation (SANE) scores, and Short Form Health Survey (SF-12) scores. Reoperation and rates of conversion to reverse shoulder arthroplasty (RSA) were determined. RESULTS: Eighty-three patients were included with an average follow-up of 56.9 ± 25.9 months (range 24-127 months). Six (7.2%) patients had additional surgery, including 3 revision rotator cuff repairs for retear, 2 conversion to RSA, and 1 capsular release and loose anchor removal. There were statistically significant improvements in shoulder ROM, ASES, SANE, VAS, and SF-12 scores postoperatively. CONCLUSION: Rotator cuff repair in select patients aged ≥75 years results in reliable improvements in pain and function. There was a low reoperation rate or conversion to RSA (7.2%) at midterm follow-up. This study indicates a role for rotator cuff repair in an elderly population and argues against the routine use of reverse arthroplasty for repairable rotator cuff tears in this population.

Treatment of elbow periprosthetic joint infection: a systematic review of clinical outcomes.

BACKGROUND: Periprosthetic joint infection (PJI) of the elbow is a relatively common complication after total elbow arthroplasty (TEA), and its treatment is frequently variable. Few articles have provided direct comparisons of outcomes, making it difficult to draw conclusions from the available literature. This systematic review synthesizes the English-language literature on elbow PJI to quantify treatment outcomes. METHODS: The PubMed and Scopus databases were searched in December 2018. Our review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Keywords included "elbow replacement infection" and "elbow arthroplasty infection." A total of 1056 titles were identified; after application of the exclusion criteria, 41 studies met the screening criteria and underwent full-text review. Fifteen articles were included for the final analysis regarding demographic characteristics, risk factors, infecting organisms, success of eradication of infection based on surgical method, and functional outcomes of specific treatment regimens. RESULTS: Among the 15 articles selected, there were 309 TEA infections. Staphylococcus aureus was the most frequently isolated organism (42.4%), followed by coagulase-negative staphylococci (32.6%). Risk factors for the development of elbow PJI included rheumatoid arthritis, steroid use, an immunocompromised state, and previous elbow surgery. The rate of successful infection eradication was highest with 2-stage revision (81.2%) and lowest with irrigation and débridement for component retention (55.8%). The level of evidence was IV in 14 studies and III in 1 study. CONCLUSIONS: In this systematic review of TEA infections, Staphylococcus species represent the most common infecting organism. Two-stage revision was the most effective treatment for elbow PJI, showing the lowest recurrence rate for infection.

Biomechanical analysis of anterior capsule reconstruction and latissimus dorsi transfer for irreparable subscapularis tears.

BACKGROUND: Anterior capsule reconstruction (ACR) and latissimus dorsi transfers (LTs) have been proposed as solutions for irreparable subscapularis tears. The purpose of this study was to biomechanically assess the effects of ACR and LT separately and together for treatment of irreparable subscapularis tears. MATERIALS AND METHOD: Eight cadaveric shoulders underwent 5 testing conditions: (1) intact, (2) irreparable subscapularis tear, (3) ACR, (4) ACR+LT, and (5) LT alone. Anteroinferior translation loads of 20, 30, and 40 N were applied. Range of motion and magnitudes of glenohumeral anterior and inferior translation at 0°, 30°, and 60° of abduction and at 30° and 60° of external rotation were measured for each testing condition. RESULTS: At 30° of abduction and 60° of external rotation, ACR and ACR+LT restored anterior and inferior translation to intact (P > .702) for 30 and 40 N of anteroinferiorly directed force. LT alone did not restore anteroinferior stability at 30 N of distraction force at 30° of glenohumeral abduction and 60° of external rotation (P < .001). However, ACR and ACR+LT led to significant decreases in total range of motion compared to intact at 0° and 30° of abduction (P < .007). CONCLUSIONS: ACR with dermal allograft was able to restore anteroinferior stability in the setting of irreparable subscapularis tears but resulted in decreased total range of motion. LT alone was less effective than ACR in restoring glenohumeral stability. The addition of LT as a dynamic restraint did not increase the efficacy of ACR.

Arthroscopic débridement of irreparable rotator cuff tears: predictors of failure and success.

HYPOTHESIS/BACKGROUND: Many techniques have been described to treat irreparable rotator cuff tears (RCT). Arthroscopic débridement for massive, irreparable RCT has been previously described to be a successful operation. The primary objective of our study was to analyze the mid-term outcomes and failure rates of arthroscopic débridement for irreparable RCTs and identify risk factors associated with failure and poor outcomes. METHODS: We retrospectively identified all patients between 2008 and 2013 who underwent arthroscopic débridement for an irreparable RCT. Demographics, operative reports, and preoperative imaging were collected from the medical record and outcome scores (American Shoulder and Elbow Surgeons [ASES] and visual analog scale) were collected at a minimum of 5-year follow-up. RESULTS: Twenty-six patients were included with a median follow-up of 98 months (range, 58-115 months). The average age at the time of surgery was 60 ± 11 years. Six patients (23%) had a reoperation at a median 11 months (range, 1-91 months), with 5 of those being revised to reverse shoulder arthroplasty. Median ASES and visual analog scale pain scores improved significantly from preoperatively to postoperatively (P < .01). Lower preoperative forward elevation was associated with worse postoperative ASES scores (P = .004) and revision to reverse shoulder arthroplasty. We found no associations between preoperative radiographic variables and reoperation or lower outcome scores. DISCUSSION/CONCLUSION: Arthroscopic débridement for irreparable RCT shows good mid-term success with improvements in patient-reported outcome scores and pain. Cost-effectiveness of more expensive procedures should be considered in the context of these successful results. Poor preoperative forward elevation appears to be a negative predictor of outcome and should be considered carefully when indicating patients for this procedure.

Failed Dermal Allograft Procedures for Irreparable Rotator Cuff Tears Can Still Improve Pain and Function: The "Biologic Tuberoplasty Effect".

BACKGROUND: Acellular dermal matrices (ADMs) have been used in the treatment of shoulders with massive rotator cuff tears (MRCTs). Despite clinical improvement, correlation of clinical findings with ADM integrity on imaging has not been investigated. HYPOTHESIS: The pain in shoulders with MRCTs is partially due to bone-to-bone contact between the tuberosity and acromion. Coverage of the tuberosity with an intact graft or a graft that is torn in a way that the tuberosity remains covered will act as an interpositional tissue, preventing bone-to-bone contact and leading to clinical improvement. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between 2006 and 2016, a total of 25 shoulders with MRCTs underwent a procedure with an ADM. Pre- and postoperative visual analog scale (VAS) results, American Shoulder and Elbow Surgeons (ASES) score, Hamada grade, and Goutallier classification were reviewed. A postoperative magnetic resonance imaging (MRI) was obtained in 22 (88%) shoulders. The status of the graft was divided into the following categories: type I, intact graft; type II, graft tear with tuberosity covered; and type III, graft tear with tuberosity uncovered (bare). RESULTS: The mean patient age was 61 years (range, 49-73 years), and the mean follow-up was 25.6 months (range, 10-80 months). Mean length from surgery to postoperative MRI was 13.9 months (range, 6-80 months). The graft was torn in 59% (13/22 shoulders). Significant improvements were found in VAS and ASES scores (7 vs 0.7 and 32.6 vs 91.2, respectively; P < .01) for type I grafts and in VAS and ASES scores (8.1 vs 1.3 and 26.3 vs 84.6, respectively; P < .01) for type II grafts. No difference was found in postoperative VAS and ASES (0.7 vs 1.3 and 91.2 vs 84.6, respectively; P = .8) between type I and type II grafts. No improvement was seen in VAS (7.3 vs 5.7; P = .2) or ASES (30.6 vs 37.2; P = .5) for type III grafts. CONCLUSION: MRI appearance of the graft has a significant impact on functional outcomes. Patients with an intact graft or a graft tear leaving the tuberosity covered have lower pain and higher functional scores than those in whom the torn graft leaves the tuberosity uncovered.

Biomechanical analysis of latissimus dorsi tendon transfer with and without superior capsule reconstruction using dermal allograft.

BACKGROUND: Irreparable rotator cuff tears (ICTs) remain a challenging treatment dilemma. Superior capsule reconstruction (SCR) acts as a static stabilizer to decrease superior humeral head migration. Latissimus dorsi tendon transfers (LDTs) dynamically decrease superior humeral head migration and improve external rotation. We hypothesized that the dynamic stabilizing effect of the latissimus transfer plus the static stabilizing effect of SCR would improve shoulder kinematics in shoulders with ICTs. MATERIALS AND METHODS: Eight fresh-frozen cadaveric shoulders were tested in 5 conditions: (1) intact, (2) ICT (supraspinatus plus anterior half of infraspinatus), (3) SCR with dermal allograft, (4) SCR plus LDT, and (5) LDT alone. Rotational range of motion, superior translation, anteroposterior translation, and peak subacromial contact pressure were measured at 0°, 30°, and 60° of glenohumeral abduction in the scapular plane. Statistical analysis was performed using a repeated-measures analysis of variance test, followed by a Tukey post hoc test for pair-wise comparisons. RESULTS: ICTs increased total shoulder rotation, superior translation, posterior translation, and peak subacromial contact pressure. SCR plus LDT significantly decreased internal rotation only at 60° of abduction. The effect of SCR plus LDT was most evident at lower levels of abduction. At the mid range of abduction (30°), the static stabilizing effect diminished but the dynamic stabilizing effect remained, allowing SCR plus LDT to reduce superior translation more effectively than SCR with dermal allograft alone. CONCLUSIONS: Adding SCR to LDT adds static stabilization to a dynamic stabilizer. Therefore, SCR plus LDT may provide additional stability at the low to mid ranges of abduction.

Gunshot Wounds to the Upper Extremity.

Upper extremity gunshot wounds result in notable morbidity for the orthopaedic trauma patient. Critical neurovascular structures are particularly at risk. The fractures are often comminuted and may be associated with a variable degree of soft-tissue injury. The literature lacks consensus regarding antibiotic selection and duration, and indications for surgical débridement. Bullets and/or bullet fragments should be removed in cases of plumbism, intra-articular location, nerve impingement, location within a vessel, and location in a subcutaneous position within the hand and/or wrist. Gunshot fractures generally do not follow common fracture patterns seen in blunt injuries, and the complexity of certain gunshot fractures can often be a challenge for the treating orthopaedic surgeon. Common plate and screw constructs may not adequately stabilize these injuries, and innovative fixation techniques may be required. The treatment for bone defects varies by location and severity of injury, and typically requires staged treatment. Nerve injuries after gunshot wounds are common, but spontaneous nerve recovery is expected in most cases.

Outpatient total elbow arthroplasty: 90-day outcomes.

BACKGROUND: Interest in outpatient arthroplasty has grown in response to increasing emphasis on the efficient delivery of safe, high-quality medical care. This study evaluated 90-day episode-of-care complications after outpatient total elbow arthroplasty (TEA). MATERIALS AND METHODS: We retrospectively evaluated 28 patients discharged the same day after primary TEA for 90-day episode-of-care complications, reoperations, and readmissions. Postoperative complications and elbow range of motion measurements were recorded and evaluated at the latest follow-up. All patients were contacted and given a satisfaction survey to assess their outpatient experience. Univariate logistic regression was performed for each risk factor to evaluate the risk for major and minor complications. Statistical significance was set as P < .05. RESULTS: Final follow-up data were available for 28 patients at an average of 14 months. Major complications within 90 days of surgery occurred in 7.1% of patients, ulnar nerve paresthesias occurred in 42.8% of patients, and minor wound problems occurred in 39.2% of patients. Five reoperations occurred after the 90-day postoperative period. All ulnar paresthesias and minor wound complications had resolved by the latest follow-up. Univariate regression analysis revealed a significant correlation between smoking and minor wound complications (P = .038). The satisfaction survey had an 85.7% response rate, with 91.7% of patients stating they were happy they went home the same day, and 95.8% feeling more confident and in control of their lives. CONCLUSIONS: The risk profile of carefully selected patients undergoing same-day discharge after TEA is acceptable when combined with close follow-up.

Vascularized dermal autograft for the treatment of irreparable rotator cuff tears.

BACKGROUND: Irreparable rotator cuff tears (IRCTs) are a challenging problem with diverse treatment modalities. We propose a technique for the treatment of IRCTs in which a vascularized dermal autograft is transferred to the posterosuperior region of the rotator cuff using the supraclavicular artery (SCA) island flap. MATERIALS AND METHODS: Dissection of 11 fresh cadavers (19 shoulders) was performed, and the SCA island flap was harvested in all specimens. A full-thickness posterosuperior rotator cuff defect was created, and the flap was tunneled under the acromion and secured into position over the defect using multiple suture anchors. Simulated flap perfusion was then assessed, and flap measurements were recorded. RESULTS: There were 4 male and 7 female cadavers (19 shoulders). Flap perfusion was assessed in 10 shoulders. On average, the flap thickness was 4.7 mm (range, 3.5-7.1 mm); width, 32.6 mm (range, 25.5-38.0 mm); and length, 169.2 mm (range, 132.0-235.0 mm). The average distance from the flap tip to the Neviaser portal was 76.2 mm (range, 48.0-99.6 mm), and that from the flap tip to the anterolateral acromial edge was 54.1 mm (range, 29.5-75.1 mm). The pedicle-to-footprint distance was 113.7 mm (range, 88.5-147.0 mm). The average flap length exceeded the pedicle-to-footprint distance by 55.5 mm (range, 43.5-88.0 mm), indicating adequate excursion of the flap. All flaps demonstrated adequate simulated perfusion after fixation. CONCLUSION: The SCA island flap may be an option for a vascularized dermal autograft for IRCTs, as shown in this cadaveric study. This illustrates a possible technique with vascular viability.

Operatively Treated Talus Fractures: Complications and Survivorship in a Large Patient Sample.

Talus fractures are relatively uncommon; however, the sequelae of talus fractures can cause significant morbidity. Although avascular necrosis has been a consistently reported complication, the reported rates of subsequent arthrodesis have varied widely. The purpose of the present study was to report the complications in a large patient sample of operatively treated talus fractures and to describe the survivorship of open reduction internal fixation (ORIF) of the talus. Patients undergoing talus ORIF for closed or open fractures from 2007 to 2011 were identified in the United Healthcare System database by International Classification of Diseases, 9th revision, code 825.21 and Current Procedural Terminology codes 28445, 28436, and 28430. Patients with a nonoperative talus fracture or isolated osteochondral defect were excluded, leaving 1527 patients in the final analysis. We also identified patients who had required subsequent subtalar, pantalar, and tibiotalocalcaneal arthrodeses using Current Procedural Terminology codes 28725, 28705, and 28715, respectively. Complications and demographic data were recorded. Of the 1527 patients, 29 (1.9%) had undergone subsequent arthrodesis within 4 years; 64 patients (4.2%) developed wound complications that did not require surgical intervention, 11 patients (0.7%) were readmitted, 204 (13.3%) presented to the emergency department (ED), and 96 (6.3%) underwent operative irrigation and debridement (I&D). The overall complication rate was 19.5%. Patients aged >34 years had a significantly greater rate of ED visits (54.7%, p = .015) and overall complications (56.8%, p < .001). In conclusion, ORIF of talus fractures has good survivorship when considering the failure of initial surgery or the requirement for secondary arthrodesis. Medical complications and hospital readmission were relatively rare; however, ED visits and infection requiring I&D were relatively common after ORIF of talus fractures.

Timing of hepatitis C antiviral therapy in patients with advanced liver disease: a decision analysis model.

Antiviral therapy for the treatment of hepatitis C virus (HCV) infection is used before and after liver transplantation. The objective of this study was to determine the most cost-effective timing for pegylated interferon/ribavirin therapy in patients with advanced liver disease infected with genotype 1 HCV. A Markov model was constructed to compare treatment strategies: (1) no treatment, (2) antiviral therapy in patients with compensated cirrhosis, (3) antiviral therapy in patients with decompensated cirrhosis, and (4) antiviral therapy in patients with progressive fibrosis due to recurrent HCV post-transplantation. Outcomes of interest included the total cost per patient, number of quality-adjusted life years (QALYs) saved, cost per QALY saved, number of deaths and hepatocellular carcinomas (HCCs), and number of transplants required. Compared to the no-antiviral treatment strategy, treatment during compensated cirrhosis increased QALYs by 0.950 and saved $55,314. Treatment during decompensated cirrhosis increased QALYs by 0.044 and saved $5511. Treatment during posttransplant advanced recurrence increased QALYs by 0.061 and saved $3223. Treatment of patients with compensated cirrhosis resulted in 119 fewer deaths, 54 fewer HCCs, and 66 fewer transplants with respect to the no-treatment strategy. The model was sensitive to the rate of graft failure in patients with and without sustained virological response. The model was otherwise robust to all variables tested in sensitivity analysis. In conclusion, the treatment of patients with compensated cirrhosis was found to be the most cost-effective strategy and resulted in improved survival and decreased cost in comparison with all other strategies. This study provides pharmacoeconomic evidence in support of treating HCV in patients with compensated cirrhosis before progression to more advanced liver disease.

Development of experimental autoimmune uveitis: efficient recruitment of monocytes is independent of CCR2.

PURPOSE: Macrophages are major contributors to the damage occurring in the retina in experimental autoimmune uveitis (EAU). CCR2 may be needed for efficient recruitment of monocytes to an inflammatory site, and the aim of this study was to determine whether this was the case in EAU. METHODS: EAU was induced and graded in C57BL/6J and CCR2(-/-) mice. Macrophage infiltration and CCR2 expression were assessed using immunohistochemistry. Retinas were examined for MCP-1 expression using RT-PCR. Rolling and infiltration of labeled bone marrow monocytes at the inflamed retinal vasculature were examined by scanning laser ophthalmoscopy and confocal microscopy, respectively. Effect of CCR2 deletion or blockade by antibody and antagonist was determined. RESULTS: Expression of mRNA for MCP-1 increased as EAU developed and was localized to the retina. CCR2 was associated with infiltrating macrophages. However, EAU induced in CCR2(-/-) mice was not reduced in severity, and neither was the percentage of macrophages in the retina. CCR2(-/-) monocytes, 48 hours after adoptive transfer to mice with EAU, showed no significant difference in percentage rolling or infiltration into the retina compared to WT. CCR2-independent rolling of monocytes was confirmed by CCR2 neutralizing antibody and antagonist treatment. CONCLUSIONS: CCR2 does not have a primary role in the recruitment of monocytes to the inflammatory site across the blood-retina barrier in well-developed EAU. Therapeutics targeting CCR2 are unlikely to be of value in treating human posterior uveitis.

Phototoxicity and fluorotoxicity combine to alter the behavior of neutrophils in fluorescence microscopy based flow adhesion assays.

The use of fluorescent probes that allow visualization of leukocyte-endothelial cell (EC) interactions has greatly informed our understanding of leukocyte recruitment. However, effects of these agents on the biological functions of leukocytes are poorly described, leading to concerns about the interpretation of such data. Here we used two flow-based neutrophil adhesion assays to compare the effects of phase contrast illumination (PCI) with high intensity illumination (HII) used for fluorescent microscopy, in the presence or absence of five commonly used fluorochromes. Isolated neutrophils were either (1) perfused across P-selectin to establish a population of rolling cells, which were subsequently activated with fMLP; or (2) perfused across EC activated with TNF-alpha. In the absence of fluorescent dyes, HII did not affect levels of leukocyte adhesion; however, subsequent neutrophil behavior was dramatically altered when compared with cells under PCI, for example, dramatically reducing their migration velocities. In the presence of fluorescent dyes, the effects of HII were exacerbated, although the precise nature of the biological effects of these probes was agent specific. Thus, for the first time, our experiments describe the effects of fluorescent microscopy on the separate stages of the neutrophil recruitment process and reveal a previously unsuspected effect of HII on neutrophil migration.

A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium.

OBJECTIVE: Rheumatoid arthritis (RA) is classically thought of as a Th1, T lymphocyte-driven disease of the adaptive immune system. However, cells of the innate immune system, including neutrophils, are prevalent within the diseased joint, and accumulate in large numbers. This study was undertaken to determine whether cells of the rheumatoid stromal microenvironment could establish an inflammatory environment in which endothelial cells are conditioned in a disease-specific manner to support neutrophil recruitment. METHODS: Human umbilical vein endothelial cells (ECs) and fibroblasts isolated from the synovium or skin of RA patients were established in coculture on opposite sides of porous transwell filters. After 24 hours of EC conditioning, the membranes were incorporated into a parallel-plate, flow-based adhesion assay and levels of neutrophil adhesion to ECs were measured. RESULTS: ECs cocultured with synovial, but not skin, fibroblasts could recruit neutrophils in a manner that was dependent on the number of fibroblasts. Antibody blockade of P-selectin or E-selectin reduced neutrophil adhesion, and an antibody against CD18 (the beta2 integrin) abolished adhesion. Blockade of CXCR2, but not CXCR1, also greatly inhibited neutrophil recruitment. Interleukin-6 (IL-6) was detectable in coculture supernatants, and both IL-6 and neutrophil adhesion were reduced in a dose-dependent manner by hydrocortisone added to cocultures. Antibody blockade of IL-6 also effectively abolished neutrophil adhesion. CONCLUSION: Synovial fibroblasts from the rheumatoid joint play an important role in regulating the recruitment of inflammatory leukocytes during active disease. This process may depend on a previously unsuspected route of IL-6-mediated crosstalk between fibroblasts and endothelial cells.