Glenoid wear and its impact on clinical results after humeral head replacement using a single prosthesis in cuff tear arthropathy with more than 8 years of follow-up.

BACKGROUND: Glenoid wear (GW) is a long-term complication after humeral head replacement (HHR) and is one of the major reasons for revision surgery. This study aimed to evaluate GW at >8 years of follow-up after HHR in patients with cuff tear arthropathy (CTA) by use of a modified classification of GW, to examine the relationship between GW and clinical outcomes, and to identify risk factors for GW progression. METHODS: This retrospective case-series study included 34 shoulders that were monitored for >8 years after HHR in patients with CTA (13 men and 21 women; mean age at surgery, 70.9 years [range, 55-82 years]). Patients were monitored for a mean of 10.3 years (range, 8.1-13.2 years). GW was classified using plain radiographs as follows: grade 0, no remarkable postoperative changes; grade 1, postoperative glenohumeral joint space narrower than preoperative glenohumeral joint space; grade 2, contact between glenoid and humeral head prosthesis; and grade 3, glenoid erosion. Grade 3 cases were further classified into the following subtypes: grade 3A, partial erosion of anterior glenoid; grade 3B, partial erosion of superior glenoid; and grade 3C, concentric erosion of glenoid. Clinical outcomes including range of motion (active flexion and active external rotation) and postoperative pain (Constant score) were compared between grade 0-2 shoulders and grade 3 shoulders, as well as between the grade 3 subtypes. Age, sex, preoperative range of motion, preoperative pain, and number of ruptured tendons were analyzed as possible risk factors for progression to grade 3. RESULTS: The final GW grade was grade 0 in 3 shoulders, grade 1 in 10, grade 2 in 6, and grade 3 in 15 (grade 3A in 2, grade 3B in 6, and grade 3C in 7). The grade 3 group had lower pain scores (10.7 ± 6.2 vs. 14.2 ± 1.9, P = .044) and limited active flexion (108.2° ± 42.3° vs. 140.6° ± 26.7°, P = .041) compared with the grade 0-2 group. Subtype comparison showed that the grade 3B group had lower pain scores (7.0 ± 6.7 vs. 15.0 ± 0.0, P = .007) and limited active flexion (80.0° ± 26.2° vs. 140.8° ± 27.5°, P = .010) compared with the grade 3C group. Limited preoperative active external rotation was an individual risk factor for grade 3 GW (odds ratio, 0.93; 95% confidence interval, 0.88-0.99; P = .009). CONCLUSIONS: In the long term (>8 years) after HHR with tendon transfer in patients with CTA, patients with the development of grade 3C GW ultimately achieve pain relief even without revision surgery whereas grade 3B GW is associated with persistent pain and might require revision surgery.

Glenoid bone resorption after Bankart repair: finite element analysis of postoperative stress distribution of the glenoid.

BACKGROUND: There are various modifications of the Bankart repair, and postoperative changes to the glenoid morphology after the repair are reported. Among the various procedures performed, a decrease in the lateral glenoid diameter might be related to the surgery that involves removal of the articular cartilage and repair of the labrum-anterior inferior glenohumeral ligament complex on the glenoid surface. This is in contrast to cases without significant bony Bankart lesions that are not on the edge of the glenoid. Thus, this study aimed to compare glenoid rim stress after Bankart repair using 2 methods of finite element analysis: a method of removing the anteroinferior cartilage and repairing the glenohumeral ligament complex on the glenoid and a method of preserving the cartilage and repairing the glenohumeral ligament complex on the glenoid edge. METHODS: Five preoperative computed tomography scans of patients with traumatic anterior instability who underwent arthroscopic Bankart repair were used. Two models simulating different surgical procedures were created as follows: in model G, a 5-mm-thick cartilage on the glenoid rim was removed between 2 and 7 o'clock, and the glenohumeral ligament complex was repaired on the medial edge of the glenoid bone where the cartilage was removed. In model E, the cartilage on the glenoid rim was not removed, and the glenohumeral ligament complex was repaired on the glenoid edge. The load stresses on the anteroinferior area of the glenoid after Bankart repair with models G and E were measured using finite element analysis. RESULTS: The stress on the glenoid at 3-4 o'clock was 3.16 MPa in model G and 6.42 MPa in model E (P = .043). The stress at 4-5 o'clock was 1.68 MPa in model G and 4.53 MPa in model E (P = .043). The stress at 5-6 o'clock was 2.26 MPa in model G and 3.93 MPa in model E (P = .043). CONCLUSION: Significantly lower load stresses were observed at the anteroinferior rim of the glenoid in model G than in model E.

Discovery of a bicyclo[4.3.0]nonane derivative DS88790512 as a potent, selective, and orally bioavailable blocker of transient receptor potential canonical 6 (TRPC6).

In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp3 carbon atoms to increase the molecular complexity, measured by fraction sp3 (Fsp3). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC50 value of 11 nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNaV1.5 channels, and was identified as an orally bioavailable compound.

Humeral bone resorption after anatomic shoulder arthroplasty using an uncemented stem.

BACKGROUND: Bone resorption around the femoral stem after total hip arthroplasty is a well-known phenomenon. However, only a few studies have evaluated bone resorption after shoulder arthroplasty. This study investigated the prevalence of humeral bone resorption after different shoulder arthroplasty procedures. METHODS: The study included 147 shoulders that underwent total shoulder arthroplasty (TSA) or humeral head replacement (HHR) with an uncemented humeral stem from November 2008 to May 2015 and were monitored for more than 1 year. The prevalence of humeral bone resorption and risk factors were investigated. RESULTS: The most advanced grade of bone resorption, grade 0, occurred in 21 shoulders (14.3%). Grade 1 bone resorption occurred in 10 (6.8%), grade 2 in 28 (19.0%), grade 3 in 61 (41.5%), and grade 4 in 27 (18.4%). High occurrence of bone absorption was observed in zones 1, 2, and 7. Grade 4 bone resorption did not occur in zones 3 and 5. HHR, on-growth type stem coating, and occupation ratio were significant independent risk factors for grade ≥3 bone resorption, whereas female sex and HHR were significant independent risk factors for grade 4. CONCLUSION: Bone resorption was observed in 126 shoulders (85.7%), and full-thickness cortical bone resorption occurred in 27 shoulders (18.4%). Bone resorption was frequently observed at the greater tuberosity, lateral diaphysis, and calcar region (zones 1, 2, and 7). Significant risk factors included female sex, HHR with rotator cuff reconstruction, on-growth type stem coating, and high occupation ratio of the implant.

Bone marrow stimulation at the footprint of arthroscopic surface-holding repair advances cuff repair integrity.

BACKGROUND: Bone marrow stimulation (BMS) at the footprint of arthroscopic rotator cuff repair has not been fully evaluated according to the preoperative tear size and surgical technique. In this study, we investigated the effect of BMS on cuff repair integrity after an arthroscopic surface-holding (ASH) repair. MATERIALS AND METHODS: A total of 111 patients (mean age, 64.5 years) with chronic rotator cuff tears who underwent treatment by the ASH method with BMS by drilling of multiple holes at the footprint (67 shoulders) or without BMS (44 shoulders) were studied, and all patients were observed prospectively. Sugaya's classification was used to evaluate cuff integrity by postoperative magnetic resonance imaging, with types IV and V classified as rotator cuff retears. RESULTS: The mean scores for cuff integrity were 2.2 ± 0.2 and 1.7 ± 0.2 in the non-BMS and BMS groups, respectively. The mean scores were similar between the 2 groups for medium tears; however, scores for large-massive tears were significantly lower in the BMS group. The overall retear rate was 23.9% in the non-BMS group and 9.1% in the BMS group, and the distribution of repair types differed significantly. For large-massive tears, the retear rate was much higher in the non-BMS group (28.6%) than in the BMS group (4.5%), although the rates for medium tears were comparable between the 2 groups. CONCLUSIONS: These findings demonstrate that applying BMS to the footprint during ASH repair results in improved cuff repair integrity, particularly in large-massive tears, and suggest the importance of biologic treatment for rotator cuff healing after arthroscopic rotator cuff repair.

Surface-holding repair: an original arthroscopic rotator cuff repair technique.

BACKGROUND: Arthroscopic rotator cuff repair provides satisfactory results; however, there is still a high rate of re-tear. The objective of this study was to present a surface-holding technique that we recently developed for arthroscopic rotator cuff repair in detail and to evaluate the clinical outcome as well as cuff repair integrity with this new method. MATERIALS AND METHODS: A consecutive series of 116 patients with full-thickness rotator cuff tears underwent arthroscopic surface-holding repair and were monitored with the Japanese Orthopaedic Association, Constant-Murley, and University of California-Los Angeles scores to assess the clinical outcome. The mean follow-up period was 17.9 months (range, 12-40 months). Cuff repair integrity was evaluated by magnetic resonance imaging. RESULTS: All 3 rating systems at the time of final follow-up reflected a significant improvement in functional recovery of the shoulder compared with the preoperative scores. The overall rate of rotator cuff retear was 19.0% (22 of 116 shoulders), and the rates were 13.6% (9 of 66 shoulders) for small and medium-sized tears and 26% (13 of 50 shoulders) for large and massive tears. The rate for large and massive tears was much higher in patients older than 70 years (58.3%) compared with those younger than 70 years (36.3%), whereas the retear rates were similar in these 2 groups (22.2% and 17.5%, respectively). CONCLUSIONS: Arthroscopic surface-holding repair technique with medial suture and transosseous fixation improved rotator cuff healing. This method may be useful both for young patients and for elderly patients, who frequently have chronic large and massive tears, including osteoporotic bones.

Suprascapular notch variations: a 3DCT study.

BACKGROUND: Although cadaveric studies have revealed suprascapular notch shape variations, few have investigated the association between suprascapular notch variation and age or gender. The purpose of this study was to investigate suprascapular notch shape variations by use of three-dimensional computed tomography (3DCT) and to determine if there was any association with age or gender. METHODS: Three-dimensional CT images of 762 shoulders of 762 patients were analyzed in this study. Participants comprised 404 men and 358 women, with an average age of 58.2 ± 19.1 years. Suprascapular notch shape variations were classified into six types on the basis of Rengachary's classification. RESULTS: Of the total study population, 11.4% were classified as type I, 23.5% as type II, 30.1% as type III, 14.8% as type IV, 15.9% as type V, and 4.3% as type VI. Average age was 56.5 ± 20.5 years for type I, 57.0 ± 19.5 years for type II, 55.5 ± 20.0 years for type III, 56.4 ± 18.5 years for type IV, 65.5 ± 14.4 years for type V, and 68.0 ± 13.4 years for type VI. Statistically significant age differences were found between types I-IV and V, between types I-IV and VI, and between the non-ossification group (types I-IV) and the ossification group (types V and VI). Male-to-female ratio among each type, and between the non-ossification group and the ossification group, were not statistically significantly different. CONCLUSIONS: Our results suggest that transverse scapular ligament ossification is associated with aging whereas individual variation explains differences among types I, II, III, and IV. Three-dimensional CT provides useful information for arthroscopic resection of the transverse scapular ligament, when the wide variety of suprascapular notch shape variations is considered. LEVEL OF EVIDENCE: Level IV.

Long-term outcomes of hemiarthroplasty using a smaller head combined with rotator cuff reconstruction in patients with cuff-tear arthropathy.

Background: Hemiarthroplasty (HHR) using a smaller head with rotator cuff reconstruction is a treatment option for cuff-tear arthropathy, offering advantages like facilitating rotator cuff-tear closure, increasing the lever arm of deltoid, and restoring function in irreparable cuff tears. This study aimed to evaluate the long-term outcomes of this procedure. Methods: A retrospective analysis was conducted for 91 shoulders undergoing HHR using a smaller head with rotator cuff reconstruction between May 2005 and September 2012. Surgery involved reducing the size of humeral head and performing rotator cuff reconstruction based on the site of the deficient rotator cuff. The study analyzed University of California, Los Angeles shoulder scores, Japanese Orthopaedics Association shoulder scores, range of motion, and postoperative radiographs. Results: Twenty-eight patients, divided into an elderly group (14 women, 2 men, mean age 74.5 ± 3.8 years) and a younger group (6 women, 6 men, mean age 63.5 ± 3.1 years) were followed up for a mean of 133.2 ± 14.1 months. No complications were reported. The clinical scores and range of motion significantly improved postoperatively and remained over 10 years. Radiographs revealed high incidence of glenoid wear (82.1%), bone resorption (43%) and cranial humeral head migration (54%), with no prosthesis loosening. Conclusion: We believe that HHR using a smaller head with rotator cuff reconstruction is a surgical technique that can maintain stable long-term outcomes in both elderly and younger individuals with cuff-tear arthropathy.

Qualitative and quantitative assessment of stent restenosis by optical coherence tomography: comparison between drug-eluting and bare-metal stents.

BACKGROUND: We hypothesized that the tissue components of in-stent restenosis (ISR) might differ between drug-eluting stents (DES) and bare-metal stents (BMS) and that these differences could be distinguished by qualitative and quantitative optical coherence tomography (OCT) analyses. METHODS AND RESULTS: One-hundred and twenty-two initial ISR lesions (sirolimus-eluting stents: n=28; paclitaxel-eluting stents: n=51; BMS: n=43) were evaluated with OCT. Based on their OCT appearance, the lesions were classified as homogeneous, layered or heterogeneous. The optical properties of backscatter, attenuation and signal intensity of the neointimal tissue (NIT) were quantified. To evaluate the vascular response after balloon angioplasty (BA), the rate of reduction of the NIT area (NITA) was calculated (NITA before - after BA/NITA before BA at the minimum lumen cross-sectional area). Among the morphologic OCT patterns, the layered type was predominant with DES, whereas lesions were homogeneous with BMS (P<0.001). Backscatter and signal intensity were significantly higher with BMS (P<0.05 and P<0.001 respectively). The NITA reduction rate was significantly greater in the layered and heterogeneous groups than in the homogeneous group (P<0.01). CONCLUSIONS: The morphologic OCT patterns of the NIT in ISR differed significantly between DES and BMS, probably reflecting pathologic differences. Layered and heterogeneous tissues might respond better than homogeneous tissue to simple balloon dilatation, suggesting a possible direction for OCT-based ISR treatment strategies.

Inhibition of thrombin-activatable fibrinolysis inhibitor via DS-1040 to accelerate clot lysis in patients with acute pulmonary embolism: a randomized phase 1b study.

BACKGROUND: The optimal treatment of intermediate-risk pulmonary embolism (PE) in hemodynamically stable patients remains unknown. Fibrinolytics reduce the risk of hemodynamic deterioration but increase bleeding risk. DS-1040, an inhibitor of thrombin-activatable fibrinolysis inhibitor, enhanced endogenous fibrinolytic activity without increasing bleeding risk in preclinical studies. OBJECTIVES: To evaluate the tolerability and explore the efficacy of DS-1040 in patients with acute PE. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study, ascending doses of intravenous DS-1040 (20-80 mg) or placebo were added to enoxaparin (1 mg/kg twice daily) in patients with intermediate-risk PE. The primary endpoint was the number of patients with major or clinically relevant nonmajor bleeding. The percentage change in thrombus volume and right-to-left ventricular dimensions, assessed using quantitative computed tomography pulmonary angiography, at baseline and after 12 to 72 hours were used to explore the efficacy of DS-1040. RESULTS: Of 125 patients with all available data, 38 were randomized to placebo and 87 to DS-1040. The primary endpoint occurred in 1 patient in the placebo group (2.6%) and 4 patients who received DS-1040 (4.6%). One subject experienced major bleeding (DS-1040 80 mg group); no fatal or intracranial bleeding occurred. Thrombus volume was 25% to 45% lower after infusion, with no differences between the DS-1040 and placebo groups. There was no difference in the change from baseline right-to-left ventricular dimensions between the DS-1040 and placebo groups. CONCLUSION: In patients with acute PE, adding DS-1040 to standard anticoagulation was not associated with an increase in bleeding but did not improve thrombus resolution or right ventricular dilation.

Impact of stent platform of paclitaxel-eluting stents: assessment of neointimal distribution on optical coherence tomography.

BACKGROUND: The Taxus Express™ paclitaxel-eluting stent (Express-PES) and Taxus Liberté™ PES (Liberté-PES) have identical drugs, drug doses, and polymers, but different stent platforms. The Liberté-PES platform has thinner struts, specifically designed for more uniform drug elution. METHODS AND RESULTS: Fifty-four patients who underwent 6-month follow-up optical coherence tomography (OCT) after Express-PES (n=27) or Liberté-PES (n=27) implantation were enrolled. Longitudinal and circumferential uniformity of neointimal distribution was evaluated in 3-D by computing mean neointimal thickness (NIT) within 360 equally spaced radial sectors for every 1-mm cross-section. After stenting, intravascular ultrasound showed that Liberté-PES had a significantly smaller maximum angle between adjacent struts, with a tendency toward a lower incidence of % length of the segment with maximum angle >90° than Express-PES. Liberté-PES had a significantly thinner mean NIT than the Express-PES with comparable frequency of uncovered struts. Longitudinal and circumferential absolute variation of NIT expressed by standard deviation of NIT from each sector was significantly smaller for Liberté-PES than for Express-PES. Liberté-PES had a tendency toward a decreased incidence of thrombus and peri-strut low-intensity areas (findings suggestive of delayed arterial healing), compared to Express-PES. CONCLUSIONS: Stent design and thickness appeared to affect neointima suppression of PES. The stent platform of the Liberté-PES may offer greater and more homogeneous reduction of neointimal proliferation spatially across the full length of the PES.

Risk factors for eccentric glenoid wear after humeral head replacement for cuff tear arthropathy.

Background: In our previous report, glenoid wear (GW) after humeral head replacement for cuff tear arthropathy was classified with modified Goya's classification (grade 0-3), and, among 3 subtypes of grade 3 (glenoid bone erosion), grade 3B (superior eccentric erosion) showed significantly more pain and limited active flexion postoperatively compared to grade 3C (concentric erosion). The purpose of this study was to detect individual risk factors for the progression to grade 3B GW. Methods: Seventy-nine shoulders in 70 patients who were followed up for a mean of 8.2 years (range, 5.0-13.2 years), including 29 men and 41 women, with a mean age at the surgery of 71.1 years (range, 54-87 years), were reviewed. Atrophy and fatty degeneration of torn cuff muscle, preoperative humeral head displacement (superior translation ratio [STR], anterior translation ratio, and other several parameters) on preoperative magnetic resonance imaging, and other individual factors were analyzed as possible risk factors. Results: GW at the final follow-up was grade 0: 5 shoulders, grade 1: 17, grade 2: 20, and grade 3: 37 (3A: 4, 3B: 22, and 3C: 11). Preoperative higher STR was defined as a risk factor for grade 3 GW (odds ratio, 35.5; 95% confidence interval, 1.8-693.0; P = .018). Comparison among the three subtypes of grade 3 showed that patients with grade 3B GW had larger STR than 3C (41.4 ± 14.2% vs. 23.5 ± 13.3 % P = .006). Conclusion: Patients with preoperative high STR are considered to have a risk for grade 3B GW, which possibly relates to poor clinical outcome and future revision.

Safety, Pharmacokinetics and Pharmacodynamics of DS-1040, in Combination with Thrombectomy, in Japanese Patients with Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: DS-1040 is a novel inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor that may have therapeutic potential in thromboembolic diseases, such as acute ischemic stroke (AIS) or pulmonary embolism. We undertook a Phase I clinical trial to investigate the safety, pharmacokinetics, and pharmacodynamics of DS-1040 in Japanese patients who were eligible for thrombectomy following AIS. METHODS: The trial enrolled patients with AIS due to large vessel occlusion, who were planned for thrombectomy within 8 h of symptom onset. Subjects were randomized to receive a single intravenous infusion of placebo or DS-1040 (0.6, 1.2, 2.4 or 4.8 mg) in a sequential-cohort design. The primary endpoints were the incidence of intracranial hemorrhage (ICH) and major extracranial bleeding within 36 and 96 h, respectively, of treatment initiation. Treatment-emergent adverse events (TEAEs) and pharmacokinetic/pharmacodynamic parameters were also assessed. RESULTS: Nine patients received placebo and 32 patients received DS-1040. There were no cases of symptomatic ICH or major extracranial bleeding with either placebo or DS-1040 after 36 and 96 h. One patient, who received DS-1040 0.6 mg, experienced a subarachnoid hemorrhage that was considered to be drug-related. Three patients died (2 placebo, 1 DS-1040), but no deaths were adjudicated as study drug-related. In vivo exposure to DS-1040 increased in proportion to dosage, but no clear dose-response relationship was seen for D-dimer levels and thrombin-activatable fibrinolysis inhibitor activity. CONCLUSIONS: Single doses of DS-1040 0.6-4.8 mg were well tolerated in Japanese patients with AIS undergoing thrombectomy. CLINICAL TRIAL REGISTRATION NUMBER: NCT03198715; JapicCTI-163164.

STELLIUM 1: First-in-man follow-up evaluation of bioabsorbable polymer-coated paclitaxel-eluting stent.

BACKGROUND: Durable polymers used for first-generation drug-eluting stents (DES) potentially contribute to persistent inflammation and late DES thrombosis. The vascular response to the Stellium stent, which is coated with an absorbable polymer for slow release of low-dose paclitaxel, was evaluated in the present study. METHODS AND RESULTS: The 37 patients with stable angina were implanted with 47 Stellium stents. Quantitative coronary angiography (QCA) was performed at baseline, and QCA and optical coherence tomography (OCT) were performed at 6 months post-implant. The primary endpoint was major adverse cardiac events (MACE). At 6 months, 1 case of MACE occurred because of total occlusion of a protected left main artery. In-stent and segment binary restenosis rates were both 0%. In-stent late loss was 0.19 ± 0.54 mm. Altogether, 5,564 struts were visualized by OCT and mean neointimal thickness was 150.03 ± 146.36 µm. The number of well-apposed struts with and without neointima overlay was 5,135 (92.29%) and 396 (7.12%), respectively. Peri-strut low intensity was observed in 518 struts (9.31%). CONCLUSIONS: This first-in-man study of the Stellium stent shows the promising possibility of bioabsorbable polymeric surface coating paclitaxel-eluting stents out to 6 months. The low rate of peri-strut low intensity suggests low cellular toxicity of the Stellium stent compared with the first-generation DES.

Comparison by optical coherence tomography of paclitaxel-eluting stents with sirolimus-eluting stents implanted in one coronary artery in one procedure. - 6-month follow-up -.

BACKGROUND: Differences between paclitaxel-eluting stents (PES) and sirolimus-eluting stent (SES) in neointimal proliferation under strictly matched conditions remain to be clarified by optical coherence tomography (OCT). METHODS AND RESULTS: Between May and December 2007, 27 patients were implanted with a PES and a SES, randomized to either the proximal or distal site in a single coronary artery, and underwent follow-up angiography and OCT examination at 6 months. The frequency of vessel wall apposition with neointima was greater for PES than for SES (92.6% vs 85.8%, P<0.01). The median (25th, 75th percentiles) neointimal thickness (NIT) in PES was significantly greater than that in SES (90 microm [25th: 40 microm; 75th: 200 microm] vs 50 microm [25th: 20 microm; 75th: 140 microm]; P<0.01). Both the average difference between the maximum and minimum NIT in each cross-section and the average difference between the maximum and minimum NIT in the longitudinal axis were larger in PES than in SES (206+/-88 vs 131+/-57 microm; P<0.001, 607+/-243 vs 400+/-185 microm; P<0.001). Low-density spots were significantly more frequently observed in PES than in SES (30.9% vs 17.0%, P=0.001). CONCLUSIONS: Compared with SES, PES had a non-uniform and larger neointimal thickness with fewer uncovered struts, and more peri-strut low-density areas.

Humeral bone resorption after reverse shoulder arthroplasty using uncemented stem.

BACKGROUND: Humeral stem loosening has gained attention as it has been identified as a cause of revision surgery in reverse shoulder arthroplasty (RSA). In RSA, humeral stem revision is very difficult if there is humeral bone loss because of stress shielding. Some studies of humeral bone resorption after anatomic shoulder arthroplasty have been published, but there are few detailed reports of humeral bone resorption after RSA. This study aimed to investigate the prevalence of humeral bone resorption after RSA procedures and to evaluate the risk factors for bone resorption. METHODS: This study included 48 shoulders that underwent RSA with an uncemented humeral stem from July 2014 to May 2017 and were followed up for more than 1 year. The prevalence of humeral bone resorption and risk factors were investigated. Logistic, multiple logistic, and multivariate logistic regression analyses were performed to evaluate the data. RESULTS: Grade 0 bone resorption, the most advanced grade, occurred in 8 shoulders (16.7%); grade 1, in 0 (0%); grade 2, in 17 (35.4%); grade 3, in 14 (29.2%); and grade 4, in 9 (18.8%). A high occurrence of bone absorption was observed in zones 1, 2, and 7. Grade 4 bone resorption did not occur in zones 3, 5, and 6. Female sex and an onlay-type stem were significant independent risk factors for grade 4 bone resorption. CONCLUSIONS: Bone resorption was frequently observed in the greater tuberosity, lateral diaphysis, and calcar region. Significant risk factors included female sex and an onlay-type stem.

Factors that influence measurements and accurate evaluation of stent apposition by optical coherence tomography. Assessment using a phantom model.

BACKGROUND: Factors influencing measurements and accurate evaluation of stent apposition by optical coherence tomography (OCT) are not established. METHODS AND RESULTS: Phantom models of known luminal sizes and lengths were evaluated by OCT under various conditions and measurements were compared with actual values. Stents implanted into phantom models were examined by OCT to validate the measurement point on the stent strut surface for accurate evaluation of stent apposition. Strut thickness was measured at 3 points (midpoint, inner and outer surfaces of the stent shadow). The precision of OCT measurements of lumen diameter and area was satisfactory when the image wire was positioned in the center, but the error and deviation were unsatisfactory when the image wire was positioned eccentrically using a low frame acquisition rate. Longitudinal OCT measurements were close to actual values under all conditions examined. Measurements from the midpoint of the stent shadow to the adjacent vessel wall surface coincided with actual stent thickness. CONCLUSIONS: Significant measurement error can occur if the image wire is positioned eccentrically with a lower frame acquisition rate than specified by the manufacturer. To accurately evaluate stent apposition, the stent surface should be measured from the center of the stent reflection.

Fibrinolytic potential of DS-1040, a novel orally available inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa).

An activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates fibrinolysis by removing C-terminal lysine/arginine residues from partially degraded fibrin. We have identified a novel low-molecular-weight inhibitor of TAFIa, DS-1040, to be potentially useful for treating thrombotic diseases. In this study, we investigated its in vitro pharmacological profile and in vivo effects in animal models of microthrombosis and bleeding. DS-1040 inhibited human TAFIa and carboxypeptidase N (CPN) in vitro with IC50 values of 5.92 and 3.02 × 106 nmol/L, respectively, suggesting that DS-1040 is highly selective for TAFIa over CPN. DS-1040 did not affect platelet aggregation and coagulation time. In a tissue factor-induced rat microthrombosis model, intravenously administered DS-1040 reduced existing fibrin clots in the lung, whereas post-treatment with enoxaparin had limited effect. Both intravenously and orally administered DS-1040 elevated plasma D-dimer levels with similar plasma exposures of DS-1040. DS-1040 significantly augmented plasma D-dimer level on top of silent dose of recombinant tissue-plasminogen activator (t-PA), suggesting DS-1040 enhances fibrinolytic activity of t-PA. In addition, DS-1040 did not prolong the tail bleeding time beyond its efficacy dose. These results indicate that DS-1040 is a potent, selective, intravenously/orally available inhibitor of TAFIa with minimum risk of bleeding. DS-1040 is a potential novel fibrinolysis enhancer useful in treating thrombotic diseases.

A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition.

Mitochondria are involved in a variety of physiological and pathological processes. Ca2+ uptake is one of the important functions of the organelle for maintenance of cellular Ca2+ homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca2+ overload into mitochondria induces mitochondrial permeability transition (MPT), a critical step for cell death. Because inhibition of MPT is a promising approach to protecting cells and organs, it is important for drug discovery to identify novel chemicals or mechanisms to inhibit MPT. Here we report upon a small-molecule compound DS44170716 that inhibits Ca2+-induced MPT in rat liver isolated mitochondria. DS44170716 protects human liver HepG2 cells from Ca2+-induced death with a level of protection similar to cyclosporin A (CsA). The inhibitory mechanism of DS44170716 against MPT is independent on PPIF, a target of CsA. DS44170716 blocks Ca2+ flux into the mitochondria by decreasing mitochondrial membrane potential, while potently inhibiting mitochondrial complex III activities and weakly inhibiting complex IV and V activities. Similarly, complex III inhibitor antimycin A, complex IV inhibitor KCN or complex V inhibitor oligomycin inhibits Ca2+ uptake of isolated mitochondria. These results show that DS44170716 is a novel class inhibitor of MPT by blocking of mitochondrial complexes and Ca2+-overload into mitochondria.

DS16570511 is a small-molecule inhibitor of the mitochondrial calcium uniporter.

In cardiac myocytes, regulation of mitochondrial Ca2+ is important for cellular signaling and cardiac contraction. Ca2+ entry into the mitochondria is mediated by a highly selective Ca2+ channel called the mitochondrial calcium uniporter, which consists of a pore-forming subunit MCU and regulatory subunits such as MICU1. Although pharmacological regulation of the mitochondrial Ca2+ influx is a promising approach to controlling the cellular functions, a cell-permeable and specific inhibitor of the mitochondrial calcium uniporter has not yet been developed. Here, we identify a novel cell-permeable inhibitor of the uniporter by a high-throughput screening of 120 000 small-molecule compounds. In our study, DS16570511 dose-dependently inhibited serum-induced mitochondrial Ca2+ influx in HEK293A cells with an IC50 of 7 µM. DS16570511 inhibited Ca2+ uptake of isolated mitochondria from human cells, rat heart and pig heart. Overexpression of hMCU or hMICU1 in HEK293A cells increased mitochondrial Ca2+ influx, and the increases were completely suppressed by the pretreatment with DS16570511. DS16570511 also blocks mitochondrial Ca2+ overload in a Langendorff perfused beating rat heart. Interestingly, DS16570511 increased cardiac contractility without affecting heart rate in the perfused heart. These results show that DS16570511 is a novel cell-permeable inhibitor of the mitochondrial calcium uniporter and applicable for control of the cardiac functions.