Incidence of Re-Dislocation/Instability After Arthroscopic Bankart Repair: Analysis via Telephone Interviews.

INTRODUCTION: Current advances in arthroscopic surgery have led to good outcomes for arthroscopic Bankart repair (ABR) for recurrent anterior shoulder dislocation. However, recent studies have reported recurrence rates of 4%-19% after ABR. In our survey conducted from February 2002 to December 2010, the post-ABR re-dislocation rate was 8.8%. In 2011, we began performing the ABR with open Bristow (B) procedure or Remplissage (R) procedure in patients with large glenoid or humeral head bone defects and in patients who play collision sports. Therefore, the present study is the second series evaluating the incidence of re-dislocation and instability after recurrent anterior shoulder dislocation. METHOD: Surgery was performed for 84 cases of shoulder instability from January 2011 to August 2017. After excluding 7 open surgeries, 6 reoperations, and 2 patients with multidirectional instability, telephone interviews were conducted with 69 patients. The average follow-up duration was 46.9 months (range, 13-92 months). RESULT: ABR alone was performed 61 patients; the B procedure was added for 3 patients, and the R procedure was added for 5 patients. Telephone interviews were conducted with 61 patients. There were no cases of re-dislocation or reoperation. Four patients who underwent only ABR experienced postoperative instability, but not to the extent that their daily lives were affected. CONCLUSION: This study showed that the addition of R or B technique to ABR for recurrent anterior shoulder dislocation resulted in a 0% re-dislocation rate.

Midterm Functional and Structural Outcomes of Large/Massive Cuff Tears Treated by Arthroscopic Partial Repair.

BACKGROUND: Previous studies have shown good clinical outcomes in patients with irreparable large or massive rotator cuff tears treated using arthroscopic partial repair (APR); however, few studies have evaluated both functional and structural outcomes in these patients. PURPOSE: To evaluate both functional and structural outcomes in patients with large or massive rotator cuff tears treated using APR. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between March 2009 and November 2016, a total of 30 patients underwent APR because of the irreparability of their large or massive rotator cuff tears during surgery. Of these patients, 24 completed the minimum 24-month follow-up (mean, 61.8 ± 27.1 months; range, 24-112 months) and were included in this study. Functional outcome measures included the Japanese Orthopaedic Association (JOA) and University of California Los Angeles (UCLA) scores and the visual analog scale for pain. Structural outcome measures comprised preoperative fatty degeneration, mediolateral tear size, residual tendon attachment area, and glenohumeral (GH) arthritic changes evaluated on magnetic resonance imaging scans or plain radiographs before and after surgery. Functional and structural outcomes were evaluated preoperatively, at 3 months postoperatively, and at the final follow-up. RESULTS: The JOA scores for all patients significantly improved from 67.9 ± 11.3 preoperatively to 85.4 ± 15.6 postoperatively (P < .0001). Similarly, the UCLA scores significantly improved from 15.8 ± 4.20 preoperatively to 29 ± 6.69 at final follow-up postoperatively (P < .0001). The mediolateral tear size were significantly decreased at 3 months postoperatively (P < .001) and at the final follow-up (P < .001). Compared with preoperative scores, the novel score evaluating the residual tendon attachment area improved from 3.08 ± 0.46 to 3.54 ± 0.41 (P < .001) after surgery overall, although it significantly deteriorated from 3 months postoperatively to the final follow-up. GH osteoarthritis progressed in 6 patients (25%). Patients who developed osteoarthritis had lower JOA and UCLA scores than did those who did not (JOA, P = .010; UCLA, P = .037). CONCLUSION: In irreparable large or massive rotator cuff tears treated using APR, functional outcome improved after surgery. Although the residual tendon attachment area improved, functional outcome after APR corresponded to the GH alterations at the midterm follow-up. Longer-term follow-up is needed to further elucidate the effect of APR on clinical outcomes in these patients.

Clinical outcomes of the Cadenat procedure in the treatment of acromioclavicular joint dislocations.

We report our clinical experience using the modified Cadenat method to treat acromioclavicular joint dislocation, and discuss the usefulness of this method. This study examined 6 shoulders in 6 patients (5 males, 1 female) who were diagnosed with acromioclavicular joint dislocation and treated with the modified Cadenat method at our hospital. Average age at onset was 49.3 years (26-78 years), average time interval from injury until surgery was 263.8 days (10 to 1100 days), and the average follow-up period was 21.7 months (12 to 42 months). Post-operative assessment was performed using plain radiographs to determine shoulder joint dislocation rate and Japanese Orthopaedic Association (JOA) score. The average post-operative JOA score was 94.1 points (91 to 100 points). The acromioclavicular joint dislocation rate improved from 148.7% (72 to 236%) before surgery to 28.6% (0 to 60%) after surgery. Conservative treatment has been reported to achieve good outcomes in acromioclavicular joint dislocations. However, many patients also experience chronic pain or a sensation of fatigue upon putting the extremity in an elevated posture, and therefore ensuring the stability of the acromioclavicular joint is crucial for highly active patients. In this study, we treated acromioclavicular joint dislocations by the modified Cadenat method, and were able to achieve favorable outcomes.

Enhancement of anti-tumor immunity by high levels of Th1 and Th17 with a combination of dendritic cell fusion hybrids and regulatory T cell depletion in pancreatic cancer.

Regulatory T cells (Tregs) play an important role in immunological self-tolerance and protect the host from autoimmune disease. However, in cancer immunity, Tregs might block anti-tumor immune responses. Therefore, the depletion of Tregs using a specific agent that suppresses its function or population, such as an anti-CD25 antibody, could promote anti-tumor immune responses. In the present study, a cytotoxicity assay, enzyme-linked immunosorbent spot (ELISPOT) assay and measuring cytokine secretion, were used to study the efficacy of Treg depletion by anti-CD25 antibody added to a dendritic cell/tumor cell (DC/TC) fusion hybrid vaccine in a murine pancreatic cancer model. All the mice treated with the combined therapy of fusion hybrid vaccine and Treg depletion rejected tumor growth in a challenging test, although the rejection rate was 20% both for mice that received the fusion hybrids alone or Treg depletion alone. In addition, combined therapy showed a significantly improved survival in comparison to other treatment or control groups. The NK cell activity for DC/TC fusion + Treg depletion was significantly higher than that for the other treatment groups. Cytotoxic T lymphocyte (CTL) activity for DC/TC could potentially be enhanced by the addition of Treg depletion therapy. The treatments including DC/TC fusion induced IFN-gamma secreting effector cells in ELISPOT assays. Furthermore, a cytometric beads array assay used to measure cytokine secretion showed that DC/TC fusion + Treg depletion stimulated the highest levels of IFN-gamma Th1/Th2 ratios and Th17. These results demonstrate that Treg depletion combined with DC/TC fusion hybrid vaccine enhanced the efficacy of immunotherapy in pancreatic cancer by activating CTLs and NK cells.

Low-dose warfarin functions as an immunomodulator to prevent cyclophosphamide-induced NOD diabetes.

Warfarin has been used as an anticoagulant for a long time. Recently, the pleiotropic effect of warfarin has been investigated. As low-dose warfarin has been reported to have anti-inflammatory effect through suppression of IL-6 secretion and inhibit the immune-associated signal between Tyro3 and its ligand, Gas6, the effect of low-dose warfarin on autoimmune diabetes in NOD mice was examined. To investigate the anti-inflammatory effect of warfarin, IL-6 secretion by splenocytes was examined in the presence of various concentrations of warfarin. Low concentration of warfarin inhibited IL-6 secretion. mRNA expression of Rse, one of the Tyro3 receptor family members, and Gas6 were analyzed in NOD mice. It was detected in islets, splenocytes and bone-marrow derived dendritic cells. 0.25 mg/l or 0.50 mg/l of warfarin was orally administered to NOD mice as a cyclophosphamide-induced diabetes model. Oral administration of warfarin at much lower doses than those clinically used as an anticoagulant significantly reduced the degree of insulitis and diabetes incidence in this model. We previously demonstrated that anti-FasL Ab-treatment led to complete prevention of autoimmune diabetes in NOD mice. As Fas/FasL signaling is reported to be essential for cyclophosphamide-induced diabetes model, we extracted RNA from lymphocytes of the inguinal lymph nodes of anti-FasL Ab-treated NOD mice and performed real-time PCR to determine expression of Rse gene. Interestingly, the expression of Rse gene related to the blockade of Fas/FasL signaling was reduced to less than half the level of untreated mice. In conclusion, low-dose warfarin is a potential immunomodulator which can prevent autoimmune diabetes.

Prevention of recurrent but not spontaneous autoimmune diabetes by transplanted NOD islets adenovirally transduced with immunomodulating molecules.

Pancreatic islet transplantation has the potential to maintain normoglycemia in patients with established type 1 diabetes, thereby obviating the need for frequent insulin injections. Our previous study showed that recombinant IL-12p40-producing islets prevented the recurrence of NOD diabetes. First, to see which immunomodulating molecule-secreting islet grafts can most powerfully prevent diabetes development in NOD mice without immunosuppressant, NOD islets were transfected with one of the following adenoviral vectors: Ad.IL-12p40, Ad.TGF-beta, Ad.CTLA4-Ig, or Ad.TNF-alpha after which they were transplanted under the renal capsule of acutely diabetic NOD mice. The immunomodulating molecules produced by these adenovirus-transfected islets in vitro were 74+/-19ng, 50+/-4ng, 821+/-31ng, and 77+/-18ng/100 islets, respectively. Transplantation of IL-12p40, TNF-alpha, and CTLA4-Ig but not TGF-beta-secreting islets displayed enhanced survival and delayed diabetes recurrence in recent-onset diabetic recipients. IL-12p40-producing islet grafts most powerfully prevented recurrent diabetes in NOD mice. In addition, local production of TNF-alpha and CTLA4-Ig significantly prolonged islet graft survival. In second series of experiment, these manipulated islets were transplanted under the renal capsule of 10-week-old NOD recipients and were also transplanted subcutaneously into 2-week-old NOD recipients. Transplantation of these islets into 2- or 10-week-old pre-diabetic mice failed to protect them from developing diabetes; in fact, transplantation of Ad.TNF-alpha-transfected islets into 2-week-old mice actually accelerated diabetes onset. Taken together, this approach was ineffectual as a prophylactic protocol. In conclusion, this study showed comparisons of the immunomodulating effects of 4 different adenoviral vectors in the same transplantation model and local production of IL-12p40, TNF-alpha and CTLA4-Ig significantly prevented recurrent diabetes in NOD mice.

Intravenous administration of proinsulin 1 or 2-expressing fiber-mutant recombinant adenovirus vector protects against the development of diabetes in NOD mice.

Insulin has been reported as a major autoantigen in both human and murine type 1 diabetes (T1D). Insulin1-knockout NOD mice with only insulin2 are protected against the development of autoimmune diabetes, suggesting that insulin1 has strong immunogenicity and insulin2 has weak immunogenicity or a possible protective role in the pathogenesis of type 1 diabetes. In this study, we have developed fiber-mutant adenovirus vectors that express murine proinsulin1 or proinsulin2 (named Ad.Pins1-RGD/Ad.Pins2-RGD) and administered those virus vectors to the NOD mouse to evaluate modulation of autoimmune responses. The intravenous administration of either Ad.Pins1-RGD or Ad.Pins2-RGD at 3 and 5 weeks of age strongly suppressed the development of overt diabetes, accompanied by a significant reduction of insulin autoantibody (IAA), and suppression of disease was similar between administration of Ad.Pins1-RGD and that of Ad.Pins2-RGD. Our study suggests that systemic administration of fiber-mutant adenovirus vectors, which induce transient expression of proinsulin, may be applicable to a gene therapy inducing tolerance to insulin.

Modification of the Rb-binding domain of replication-competent adenoviral vector enhances cytotoxicity against human esophageal cancers via NF-kappaB activity.

A replication-competent adenoviral vector deficient for expression of the early E1B55K protein has been applied in clinical studies. The vector, however, was not fully effective for the treatment of human cancer. In this study, the E1A gene (which encodes an Rb-binding domain protein) of the adenoviral vector AxE1AdB was further engineered with a point mutation designed to abolish binding to Rb protein (pRb) and arrest the cell cycle (AxdAdB-3). The difference in the cytotoxicity of these vectors in two cancer cell lines was observed in association with differences in replication, infection efficiency, and expression levels of adenovirus receptors. Relative to the parent vector (AxE1AdB), which worked in a manner similar to ONYX-015, AxdAdB-3 with the mutated pRb-binding motif demonstrated increased cytotoxicity against p53-mutant human esophageal cancer cell lines EC-GI-10 and T.Tn. AxdAdB-3 showed a greater oncolytic effect than AxE1AdB in vivo despite almost the same replication efficiency in vitro. Unexpectedly, cell cycle arrest in AxdAdB-3-infected cells was less efficient than that in cell lines infected with AxE1AdB. However, AxdAdB-3 strongly reduced NF-kappaB activity and thereby enhanced apoptosis more than AxE1AdB did. These data demonstrate that the Rb-binding domain of E1A can regulate NF-kappaB activity and that modifications to this domain may lead to advances in gene therapies for the treatment of human cancers.

Nondepleting anti-CD4 monoclonal antibody prevents diabetes and blocks induction of insulin autoantibodies following insulin peptide B:9-23 immunization in the NOD mouse.

INTRODUCTION: Insulin peptide B:9-23 is a major autoantigen in type 1 diabetes that induces insulin autoantibodies and prevents diabetes in the NOD. However, immunization with peptide without adjuvant may be insufficient to reverse disease or induce long-term tolerance. Furthermore, recent experience has demonstrated the potential dangers of disease exacerbation or anaphylaxis with peptide immunotherapy. METHODS: Combination therapy of B:9-23 with a nondepleting anti-CD4 monoclonal antibody (YTS 177.9) was studied in female NOD mice from 4 through 6 weeks of age. Injections of either B:9-23 in saline, YTS 177.9 antibody, or both peptide and antibody were given to mice. RESULTS: By 52 weeks follow-up, 40% of B:9-23-treated, 100% of YTS177.9-treated, and 70% of B:9-23 and YTS177.9 combination-treated mice remained diabetes-free. IAA, both spontaneous and induced by B:9-23, was almost completely suppressed in mice receiving YTS 177.9. In addition to suppression of IAA expression, anti-B:9-23 peptide antibodies are also suppressed in mice receiving B:9-23 with YTS 177.9, compared to B:9-23 alone. CONCLUSION: A brief course of the nondepleting anti-CD4 monoclonal antibody (YTS 177.9) in NOD mice confers long-term protection from diabetes and insulitis and profoundly blocks spontaneous and B:9-23 peptide-induced insulin autoantibodies.

Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide.

Polyinosinic-polycytidylic acid (PolyIC), a "mimic" of double-stranded viral RNA, can induce diabetes when administered to rats with RT1(u), and immunization of normal H-2(d) mice (e.g., BALB/c) with insulin B:9-23 peptide (but not H-2(b)) results in the rapid induction of insulin autoantibodies. Because a mouse model of PolyIC/antigen-induced diabetes is lacking, we sought to produce insulitis and diabetes with either PolyIC and/or B:9-23 peptide immunization. Simultaneous administration of PolyIC and B:9-23 peptide to BALB/c mice (but with neither alone) induced insulitis. CD4 T lymphocytes predominated within islets, and the mice did not progress to hyperglycemia. Islets with transgene-induced expression of the costimulatory B7-1 molecule have enhanced diabetes susceptibility. Diabetes was frequently induced in B7-1 transgenic mice with H-2(d) in contrast to H-2(b) mice after PolyIC administration. Disease induction was accelerated by adding B:9-23 immunization to PolyIC. These studies demonstrate that "normal" mice have autoreactive T lymphocytes able to rapidly target islets and insulin given appropriate MHC alleles and that a peripherally administered insulin peptide (an altered peptide ligand of which is in clinical trials) can enhance specific anti-islet autoimmunity. These first PolyIC/insulin-induced murine models should provide an important tool to study the pathogenesis of type 1 diabetes with experimental autoimmune diabetes.