Safety of intranasal insulin administration in patients undergoing cardiovascular surgery: An open-label, nonrandomized, dose-escalation study.

Objective: This study aimed to determine the maximum safe dose of intranasal insulin administration during cardiac surgery. Methods: This open-label, Phase 1, single-center, dose-escalation clinical trial recruited patients scheduled to undergo elective cardiac surgery or major vascular surgery requiring cardiopulmonary bypass between February and September 2021. They were grouped into 5 dose-escalation cohorts and administered 0, 40, 80, 160, and 240 IU insulin (n = 6 in each group) via a metered nasal dispenser after the induction of general anesthesia. Blood samples were collected at 10-minute intervals for the first 60 minutes and at 30-minute intervals thereafter. Hypoglycemia was defined as a blood glucose level <70 mg/dL. Patient recruitment was terminated after hypoglycemia was observed in 2 patients in any of the groups. Results: In total, 27 of 29 enrolled patients were administered intranasal insulin or saline. Hypoglycemia was not observed after the administration of intranasal insulin in the 0, 40, 80, or 160 IU groups; however, it was observed in 2 of 3 patients in the 240 IU group. The serum insulin concentration was elevated in the 160-IU group, but the C-peptide concentration was not elevated in any of the groups. Conclusions: The administration of up to 160 IU intranasal insulin did not induce clinically significant hypoglycemia. However, 160 IU intranasal insulin should be administered cautiously because insulin can enter the systemic circulation in a dose-dependent manner.

The Results of Hook Plate Fixation for Palmar Fracture Dislocation of the Proximal Interphalangeal Joint.

PURPOSE: This study aimed to present the clinical outcomes of the dorsal plating technique for palmar fracture dislocations of the proximal interphalangeal (PIP) joint. This plating technique minimizes dissection and interference with the finger extensor mechanism. METHODS: We treated seven patients (with a mean age of 39.1 years) with dorsal hook plates for palmar fracture dislocations of the PIP joint between April 2018 and August 2022. The little finger was affected in five patients, and ring finger was affected in two. The mean time to surgery was 5.6 days, and the postoperative follow-up period was seven months. On the second postoperative day, all patients were allowed active motion of both the PIP and the distal interphalangeal (DIP) joints. Simultaneously, DIP blocking exercises were started to prevent adhesion of the extensor mechanism. RESULTS: The mean active flexion and extension of the PIP joint was 105° and -4°, respectively, whereas those of the DIP joint were 65° and 4°. No patient experienced extension lag in the DIP joint. The mean total active motion (TAM) was 273°, and the %TAM was 96%. The grip strength of the affected hand averaged 90% of that of the unaffected hand. The mean numerical rating scale for pain was 0.3 points, and the mean Hand20 score was 5.1 points. No complications were observed; two patients underwent implant removal at their request. CONCLUSIONS: The present study suggests that this hook plate technique, which minimizes interference with the finger extension mechanism, is an effective surgical procedure that allows patients to tolerate early range of motion exercises and obtain satisfactory clinical outcomes in both the PIP and DIP joints. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Role of the protein kinase A signaling pathway and identification of mediators in the cardioprotective effects of enteral lactoferrin for ischemia-reperfusion injury in an isolated rat heart model.

OBJECTIVE: Lactoferrin is an iron-binding glycoprotein. Enteral lactoferrin attenuates myocardial ischemia-reperfusion (IR) injury, but the underlying mechanism remains unknown. The aim of this study was to investigate protein kinase A (PKA) signaling pathway activation and levels of serum glucagonlike peptide-1 (GLP-1), secreted by intestinal endocrine L cells, and adiponectin, secreted by adipose tissue, after enteral lactoferrin administration. METHODS: Hearts (N = 32) were excised from Wistar rats and perfused using a Langendorff system. To assess the role of the PKA pathway in the cardioprotective effects of lactoferrin, an inhibitor of PKA (H89) was applied before no-flow ischemia. Rats were randomly divided into four groups: control, lactoferrin (LF), control+H89, and LF+H89. The control and control+H89 groups were administered normal saline by gavage, and the LF and L +H89 groups were administered bovine lactoferrin (1000 mg/kg) by gavage 15 min before intraperitoneal pentobarbital injection. Muscle sampling was performed at the end of reperfusion. When rats were sacrificed, blood was sampled to measure hormone levels. The primary outcome was maximum left ventricular pressure derivative (LV dP/dt max) 15 min after reperfusion. RESULTS: LV dP/dt max at 10 and 15 min after reperfusion was significantly higher in the LF group than in the control group (P < 0.05), and the effect was diminished by H89. The PKA pathway was significantly activated in the LF group. Enteral lactoferrin increased serum GLP-1 but not serum adiponectin levels. CONCLUSIONS: Enteral lactoferrin induces cardioprotective effects against myocardial IR injury via the PKA signaling pathway and increases serum GLP-1 levels.

Predictors of postoperative complications of tension band wiring techniques for patella fracture: A retrospective multicenter (TRON group) study.

OBJECTIVE: The relationship between postoperative complications and operative techniques of tension band wiring (TBW) is not well studied. We aimed to evaluate the incidence of implant breakage, implant migration, and loss of reduction in patellar fractures treated with TBW and identify radiographic factors associated with these postoperative complications. METHODS: This multicenter (named, TRON group) retrospective study included 224 patients who underwent open reduction and internal fixation of patella fractures using TBW from January 2016 to December 2020. Radiographic findings were evaluated by experienced orthopedic surgeons, and radiographic outcomes were assessed for K-wire migration, implant breakage, and loss of reduction. Logistic regression analysis was performed to identify radiographic factors associated with postoperative complications. RESULTS: Implant migration occurred in 44 cases (19.6%), with bending of a single K-wire end identified as a significant risk factor (OR: 12.90; 95% CI: 4.99-33.30; P < 0.001). Implant breakage occurred in 43 cases (19.2%), with a large patella-tension band ratio (OR: 291.0; 95% CI: 19.60-4330; P < 0.001) and a wide distance between K-wires (OR: 1.15; 95% CI: 1.060-1.250; P = 0.001) identified as significant risk factors. Loss of reduction occurred in 5 cases (2.0%), but no significant risk factors were identified. CONCLUSION: This study highlights the importance of bending both ends of the K-wires and proper placement of the tension band and K-wires in reducing postoperative complications in patellar fractures treated with TBW. Further research is needed to better understand the risk factors associated with loss of reduction.

Comparing Clinical and Aesthetic Outcomes of Digital Artery Flap using Nail Bed Graft for Fingertip Amputation with Replantation.

BACKGROUND: Digital artery flap (DAF) with nail bed graft is a simple method to preserve finger length for fingertip amputations. This study compared the clinical and aesthetic outcomes between replantation and DAF. METHODS: Patients who underwent replantation or DAF for a single fingertip amputation (Ishikawa's subzone II or III) at our hospital from 2013 to 2021 were retrospectively evaluated. The aesthetic and functional outcomes were finger length and nail deformity at the final follow-up, total active motion, grip strength, Semmes-Weinstein monofilament test (S-W), fingertip injuries outcome score (FIOS), and Hand20 scores. RESULTS: Overall, for 74 analyzed cases (40, replantation; 34, DAF), the median operation time and the median length of hospital stay in replantation was longer than that in DAF (188 vs. 126 min, p<0.01; 15 vs. 4 days, p<0.01). The success rates of replantation and DAF were 82.5% and 94.1%, respectively. The rate of finger shortening in replantation was significantly lower than that in DAF (42.5% vs. 82.4%; p<0.01). There were fewer nail deformities in replantation than in DAF (45.0% vs. 67.6%, p=0.06). The proportion of patients who achieved excellent or good FIOS and the median Hand20 scores was not significantly different between the groups (89.5% vs. 85.3%, p=0.61; 8.0 vs. 13.5, p=0.42). The median postoperative S-W values were similar between the groups (3.61 vs. 3.61, p=0.23). CONCLUSIONS: In this retrospective study, DAF for fingertip amputations achieved equivalent postoperative functional outcomes and shorter intraoperative time and hospital stay, but worse aesthetic appearance compared with replantation.

Ulnar Nerve Neuropathy After Surgery for Intraarticular Distal Humerus Fractures: An Analysis of 116 Patients.

PURPOSE: To identify the incidence and the factors associated with a postoperative ulnar nerve neuropathy in patients who had undergone open reduction and internal fixation for intraarticular distal humerus fractures. METHODS: We retrospectively reviewed 116 patients who had undergone surgery between January 2011 and December 2020. Age, sex, BMI, mechanism of injury, open or closed fracture, operation time, tourniquet time, and nerve injury at the final examination were collected from medical charts. We essentially used the paratricipital approach. In cases in which the reduction of intraarticular bone fragments was difficult, olecranon osteotomy was used. Ulnar nerve function was graded according to a modified system of McGowan. We conducted logistic regression analysis to investigate factors of neuropathy using items identified as statistically significant in univariate analysis as explanatory variables. RESULTS: Thirty-four patients (29.3%) had persistent neuropathy at the final follow-up. In the modified McGowan classification, 28 patients had grade 1 and 6 patients had grade 2 neuropathy. Olecranon osteotomy emerged as a distinct explanatory variable for the prophylaxis of ulnar nerve neuropathy in the multivariate analysis (odds ratio, 0.30; 95% confidence interval, 0.12-0.73). Anterior transposition, however, was not a statistically significant factor (odds ratio, 1.91; 95% confidence interval, 0.81-4.56). CONCLUSIONS: Olecranon osteotomy was the only independent factor associated with preventing the occurrence of ulnar nerve neuropathy. Ulnar nerve transposition might not be associated with prevention of ulnar nerve neuropathy. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Mortality and clinical outcomes of Vancouver type B periprosthetic femoral fractures : a multicentre retrospective study.

AIMS: The objectives of this study were to investigate the patient characteristics and mortality of Vancouver type B periprosthetic femoral fractures (PFF) subgroups divided into two groups according to femoral component stability and to compare postoperative clinical outcomes according to treatment in Vancouver type B2 and B3 fractures. METHODS: A total of 126 Vancouver type B fractures were analyzed from 2010 to 2019 in 11 associated centres' database (named TRON). We divided the patients into two Vancouver type B subtypes according to implant stability. Patient demographics and functional scores were assessed in the Vancouver type B subtypes. We estimated the mortality according to various patient characteristics and clinical outcomes between the open reduction internal fixation (ORIF) and revision arthroplasty (revision) groups in patients with unstable subtype. RESULTS: The one-year mortality rate of the stable and unstable subtype of Vancouver type B was 9.4% and 16.4%. Patient demographic factors, including residential status and pre-injury mobility were associated with mortality. There was no significant difference in mortality between patients treated with ORIF and Revision in either Vancouver B subtype. Patients treated with revision had significantly higher Parker Mobility Score (PMS) values (5.48 vs 3.43; p = 0.00461) and a significantly lower visual analogue scale (VAS) values (1.06 vs 1.94; p = 0.0399) for pain than ORIF in the unstable subtype. CONCLUSION: Among patients with Vancouver type B fractures, frail patients, such as those with worse scores for residential status and pre-injury mobility, had a high mortality rate. There was no significant difference in mortality between patients treated with ORIF and those treated with revision. However, in the unstable subtype, the PMS and VAS values at the final follow-up examination were significantly better in patients who received revision. Based on postoperative activities of daily life, we therefore recommend evision in instances when either treatment option is feasible.Cite this article: Bone Jt Open 2023;4(1):38-46.

Reasons and risk factors for discontinuation of treatment with any biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: A long-term observational study.

OBJECTIVES: Patients with rheumatoid arthritis (RA) usually switch to a second biological disease-modifying antirheumatic drugs (bDMARDs) when the first has proven to be ineffective, although some may discontinue bDMARDs treatment altogether. We investigated the total rate of bDMARDs retention and the risk of bDMARDs discontinuation in patients with RA. METHODS: The study included 564 patients with RA who started bDMARDs treatment before 2008 (<65 years old, n = 413; ≥65, n = 151). The primary outcome was the incidence of bDMARDs discontinuation due to adverse events (AEs). Risk factors were examined using Fine and Gray regression models. RESULTS: Among 564 patients, 74 had discontinued bDMARDs treatment due to AEs. Male sex and Steinbrocker class 3-4 were more frequent, while rheumatoid factor and concomitant methotrexate treatment were less frequent, in those aged ≥65 years than in those aged <65 years, respectively. The subdistribution hazard ratio for discontinuation was significantly higher in the ≥65 group than in the <65 years group (hazard ratio = 3.53, 95% confidence interval = 2.07-6.03). Lack of concomitant treatment with MTX was risk factor for discontinuation in patients ≥65 years. Advanced Steinbrocker class was a risk factor in patients <65 years. CONCLUSIONS: Older patients are at higher risk of discontinuing bDMARDs treatment due to AEs than younger patients.

Effectiveness of tacrolimus concomitant with biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

OBJECTIVES: The study aimed to investigate the effectiveness and tolerance of biological disease-modifying antirheumatic drugs (bDMARDs) therapy administered concomitantly with tacrolimus (TAC) treatment in patients with rheumatoid arthritis. METHODS: 2792 patients who underwent therapy with five bDMARDs (etanercept: ETN, adalimumab, golimumab, tocilizumab, and abatacept: ABT) were enrolled. Among the study subjects, 1582 were concomitant methotrexate (MTX group), 147 were concomitant TAC (TAC group), and 1063 were non-concomitant MTX and TAC (non-MTX/TAC group). The primary outcome was the incident rate of discontinuation of bDMARDs by adverse events (AEs) or loss of efficacy. RESULTS: Concerning the analysis for each reasons of discontinuation, including AEs and loss of efficacy, the hazards ratio (HR) was significantly lower in the TAC group than in non-MTX/TAC groups (AEs: HR = 0.39, 95% confidence interval, 0.23-0.68, loss of efficacy: HR = 0.49, 95% confidence interval, 0.30-0.78). The loss of efficacy with the use of ETN and ABT was lower in the TAC group than in non-MTX/TAC groups. Concomitant TAC did not induce elevated risk for discontinuation of AEs in all bDMARD analyses. CONCLUSIONS: Concomitant TAC with ABT or ETN showed higher retention rates than bDMARDs therapy without TAC or MTX. AEs did not increase over long-term observation.

Cardioprotective effects of enteral vs. parenteral lactoferrin administration on myocardial ischemia-reperfusion injury in a rat model of stunned myocardium.

BACKGROUND: Lactoferrin, an iron-binding glycoprotein, is known to have protective effects against intestinal and cerebral ischemia-reperfusion (IR) injuries; however, its cardioprotective effects against the stunned myocardium are unknown. This study aimed to test the hypothesis that lactoferrin has cardioprotective effects against stunned myocardium. METHODS: Using isolated rat hearts (Langendorff system), we determined the effects of lactoferrin administered enterally and by direct cardiac perfusion. Rat hearts were perfused using the Langendorff system, and two experiments were performed. In experiment 1, the hearts were divided into the enteral lactoferrin (E-LF) 7.5 m, 15 m, 30 m, and 60 m groups, where lactoferrin (1000 mg/kg) was administered enterally 7.5, 15, 30, and 60 min, respectively, before perfusion; and a control group, where saline was administered 30 min before perfusion. In experiment 2, hearts were allocated to the perfusate lactoferrin (P-LF) 15 and 100 groups, where 15 mg/L and 100 mg/L lactoferrin were respectively added to the perfusate, and a control group. Each group was perfused for 20 min prior to 15 min of no-flow ischemia with pacing, followed by 20 min of reperfusion. The primary outcome was the maximum left ventricular derivative of pressure development (LV dP/dt max) 15 min after reperfusion. Myocardial phospho-protein kinase B (p-Akt) was assayed using western blotting. RESULTS: The LV dP/dt max 15 min after reperfusion in the E-LF 15 and 30 m groups was significantly higher than that in the control group. However, the effects disappeared in the E-LF 60 m group. In the second experiment, there were no significant differences in LV dP/dt max. Myocardial p-Akt was not significantly activated in any lactoferrin group. CONCLUSION: Cardioprotection was observed 15-30 min after enteral lactoferrin but not by direct cardiac perfusion with lactoferrin. Myocardial p-Akt was not associated with the cardioprotective effect. The cardioprotective effect may be induced by enteral lactoferrin-induced substances.

A macroscopic anatomical study of the appropriate palpation zone of the gluteus medius muscle.

[Purpose] Few previous studies have delimitated the palpation zone of the gluteus medius muscle with a focus on its fiber bundles. The purpose of this study was to clarify the morphological characteristics of the gluteus medius muscle using an anatomical approach, and to define its proper palpation zone. [Participants and Methods] In this study, we evaluated thirteen halves of the pelvic region in seven formalin-fixed cadavers. We identified the borders between the iliotibial band and gluteus medius muscle, and between the gluteus medius and gluteus maximus muscles, on the iliac crest. Furthermore, we quantified the border points of the gluteus medius' fiber bundles and observed its anatomical and morphological characteristics. [Results] We identified two fiber bundles in the gluteus medius muscle, an anterior and a posterior fiber bundle, and detected that a portion of the posterior fibers was located subcutaneously. [Conclusion] We propose that the region where the posterior fibers of the gluteus medius muscle are located subcutaneously is an appropriate zone for the palpation of this muscle.

PI3K/Akt pathway mediates the positive inotropic effects of insulin in Langendorff-perfused rat hearts.

Insulin exerts positive inotropic effects on cardiac muscle; however, the relationship between cardiac contractility and phosphoinositol-3-kinase/Akt (PI3K/Akt) activation remains unclear. We hypothesized that the positive inotropic effects of insulin are dose-dependent and mediated via the PI3K/Akt pathway in isolated normal rat hearts. The Institutional Animal Investigation Committee approved the use of hearts excised from rats under pentobarbital anesthesia. The hearts were perfused at a constant pressure using the Langendorff technique. After stabilization (baseline), the hearts were randomly divided into the following four insulin (Ins) groups: 1) Ins0 (0 IU/L), 2) Ins0.5 (0.5 IU/L), 3) Ins5 (5 IU/L), and 4) Ins50 (50 IU/L) (n = 8 in each group). To clarify the role of the PI3K/Akt pathway in insulin-dependent inotropic effects, we also treated the insulin groups with the PI3K inhibitor wortmannin (InsW): 5) InsW0 (0 IU/L), 6) InsW0.5 (0.5 IU/L), 7) InsW5 (5 IU/L), and 8) InsW50 (50 IU/L). Hearts were perfused with Krebs-Henseleit buffer solution with or without wortmannin for 10 min, followed by 20 min perfusion with the solution containing each concentration of insulin. The data were recorded as the maximum left ventricular derivative of pressure development (LV dP/dt max). Myocardial p-Akt levels were measured at 3 min, 5 min, and at the end of the perfusion. In the Ins groups, LV dP/dt max in Ins5 and Ins50 increased by 14% and 48%, respectively, 3 min after insulin perfusion compared with the baseline. Tachyphylaxis was observed after 10 min in the Ins5 and Ins50 treatment groups. Wortmannin partially inhibited the positive inotropic effect of insulin; although insulin enhanced p-Akt levels at all time points compared with the control group, this increase was suppressed in the presence of wortmannin. The positive inotropic effect of insulin is dose-dependent and consistent with Akt activation. This effect mediated by high doses of insulin on cardiac tissue was temporary and caused tachyphylaxis, potentially triggered by Akt overactivation, which leads beta 1 deactivation.

Anesthetic experience does not reduce accidental dural puncture in surgical patients: a retrospective case-controlled study.

BACKGROUND: Accidental dural puncture (ADP), which is a complication of epidural anesthesia, still exists and leads to worse outcomes in surgical patients. While residency training is important for epidural competency, it remains unknown whether anesthetic experience reduces ADP in surgical patients. Using an incident reporting system along with anesthetic records, this case-controlled study retrospectively investigated risk factors associated with ADP in surgical patients. METHODS: Patients who experienced ADP during epidural anesthesia who were registered in the incident reporting system of our institution between April 2012 and March 2019 were enrolled. Patients with ADP were control-matched with those who without ADP in a 1:3 ratio, to compare the potential risk factors and calculated odds ratios (ORs) for ADP. The primary hypothesis was that anesthesiologists' experience reduces the incidence of ADP. The secondary hypothesis was that there are risk factors for ADP. Between-group differences in anesthesiologists' experience were compared using the Mann-Whitney U test. Significance was set at P < 0.05. RESULTS: Thirty-five patients who experienced ADP were identified from the incident reporting system. These were matched with 69 patients who did not experience ADP. There was no difference in the years of experience of anesthesiologists between the groups that did and did not experience ADP (8 [3-20] vs. 9 [3-18] years, respectively; P = 0.65). CONCLUSIONS: Having an experienced anesthesiologist did not guarantee the prevention of ADP. Daily individual training and briefings would be needed to reduce the incidence of ADP.

Comparison of novel DXA system, Shimazu SONIALVISION G4, with GE-Lunar PRODIGY.

INTRODUCTION: SONIALVISION G4 (Shimadzu, Kyoto, Japan) is a fluoroscopic imaging system capable of dual-energy X-ray absorptiometry (DXA) using the additional application. However, bone mineral density (BMD) with this system is calibrated only by a phantom, and the necessity to confirm the reliability of BMD measurement in human subjects has been pointed out. This study aimed to evaluate the clinical reliability of BMD measurement using SONIALVISION G4 by comparing it with PRODIGY (GE Healthcare, Madison, WI, USA), a reference system in developing the DXA application. MATERIALS AND METHODS: BMD measurements using these two DXA systems were performed on the same day at the lumbar spine and bilateral proximal femur of 130 subjects aged 22-86 years. The agreement and correlation between the measurements were determined. Thirty out of the 130 subjects were scanned twice to determine the precision of the SONIALVISION G4 system. RESULTS: BMD was highly correlated between the two DXA systems both at the lumbar spine and proximal femur, with correlation coefficients ranging from 0.963 (left total hip) to 0.989 (left femoral neck). Differences in BMD measured by the two systems were less than 3.0%, but a small proportional bias was observed in the Bland-Altman analysis. Coefficients of variation in BMD measurement were 1.77% in the lumbar spine and 1.41-2.76% in the proximal femur. CONCLUSIONS: Although BMD values by SONIALVISION G4 were close to those by PRODIGY, follow-up studies should be performed using the same device because of the small difference between devices.

Higher doses of methotrexate associated with discontinuation of oral glucocorticoids after initiation of biological DMARDs: A retrospective observational study based on data from a Japanese multicenter registry study.

OBJECTIVE: Glucocorticoids are important drugs used to treat rheumatoid arthritis. We recommend glucocorticoid discontinuation as soon as possible given the associated side-effects, but many patients continue to take oral glucocorticoids long-term. The present study aimed to explore factors associated with glucocorticoid discontinuation at 52 weeks after initiating biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: Subjects were 564 patients from a Japanese multicenter registry who were administered glucocorticoids and methotrexate (MTX) followed by initiation of the first bDMARD. We examined the status of oral glucocorticoid use at 52 weeks after initiating the first bDMARD. RESULTS: By 52 weeks after bDMARD initiation, 164 patients (29.1%) discontinued glucocorticoids. Multivariable analysis identified age, MTX dose, and glucocorticoid dose as factors independently associated with glucocorticoid discontinuation. After adjusting for baseline characteristics using propensity score matching, among patient groups administered MTX ≤ 8 mg/week and MTX > 8 mg/week, 105 pairs remained. A significantly higher rate of glucocorticoid discontinuation (41.0%) was noted for patients administered MTX > 8 mg/week. CONCLUSION: Our findings suggest that glucocorticoids may be discontinued after initiating bDMARDs. Moreover, higher MTX doses (>8 mg/week) at the time of bDMARD initiation were associated with glucocorticoid discontinuation among patients treated with bDMARDs.

Ulinastatin attenuates protamine-induced cardiotoxicity in rats by inhibiting tumor necrosis factor alpha.

Protamine causes cardiac depression, which may be mediated by tumor necrosis factor alpha (TNF-α). Ulinastatin, a human urinary protease inhibitor, inhibits TNF-α. Here, we aimed to investigate whether ulinastatin prevented protamine-induced myocardial depression by inhibiting TNF-α. Rat hearts were perfused using a Langendorff system, and three protocols were followed. Protocol 1: The hearts were divided into saline, ulinastatin-low, and ulinastatin-high groups. Protamine was administered to each group, and myocardial contractility was the primary outcome. Protocol 2: The hearts were allotted to saline or ulinastatin group. Protamine was administered to each group. TNF-α expression in the coronary effluent and myocardial tissue was measured. Protocol 3: The hearts were allotted to saline and ulinastatin groups. Recombinant rat-TNF-α was administered to each group. Protamine alone reduced the maximum left ventricular pressure derivative (LV dP/dt max) by 45 ± 4%. In contrast, the reduction in LV dP/dt max was 4 ± 3% in the ulinastatin-high group. Compared with that in the saline group, the increase in TNF-α in the coronary effluent was attenuated in the ulinastatin group. Recombinant TNF-α alone reduced LV dP/dt max (- 21 ± 14%). In contrast, when TNF-α was added in the presence of ulinastatin, the decrease in LV dP/dt max was prevented significantly (- 3 ± 8%). We showed, for the first time, that ulinastatin protected against protamine-induced myocardial damage, both by inhibiting TNF-α synthesis and by directly preventing the cardiodepressant action of TNF-α.

A retrospective analysis of the relationship between anti-cyclic citrullinated peptide antibody and the effectiveness of abatacept in rheumatoid arthritis patients.

This study aimed to evaluate the effectiveness of abatacept (ABA) by anti-cyclic citrullinated peptide (ACPA) status on disease activity as well as radiographic progression in patients with rheumatoid arthritis (RA) in clinical settings. A retrospective cohort study was conducted using data from a multicenter registry. Data from a total of 553 consecutive RA patients treated with intravenous ABA were included. We primarily compared the status of disease activity (SDAI) and radiographic progression (van der Heijde modified total Sharp score: mTSS) between the ACPA-negative (N = 107) and ACPA-positive (N = 446) groups. 'ACPA positive' was defined as ≥ 13.5 U/mL of anti-CCP antibody. Baseline characteristics between groups were similar. The proportion of patients who achieved low disease activity (LDA; SDAI ≤ 11) at 52 weeks was significantly higher in the ACPA-positive group. Multivariate logistic regression analysis identified ACPA positivity as an independent predictor for achievement of LDA at 52 weeks. Drug retention rate at 52 weeks estimated by the Kaplan-Meier curve was significantly higher in the ACPA-positive group. Achievement rate of structural remission (ΔmTSS ≤ 0.5) at 52 weeks was similar between groups. ABA treatment demonstrated a significantly higher clinical response and higher drug retention rate in ACPA-positive patients. Progression of joint destruction was similar between the ACPA-negative and ACPA-positive groups. Close attention should be paid to joint destruction even in patients showing a favorable response to ABA, especially when the ACPA status is positive.

Improvement in matrix metalloproteinase-3 independently predicts low disease activity at 52 weeks in bio-switch rheumatoid arthritis patients treated with abatacept.

OBJECTIVES: To explore predictive factors including MMP-3 for achievement of low disease activity (LDA) at 52 weeks in bio-switch rheumatoid arthritis (RA) patients treated with abatacept, for whom obtaining a good clinical response can be difficult. METHODS: Participants were 423 consecutive patients with RA treated with abatacept who were observed for longer than 52 weeks and registered in the TBCR, a Japanese multicentre registry system. Multivariate logistic regression analysis was used to study factors that predict the achievement of LDA at 52 weeks in bio-naïve (n=234) and bio-switch (n=189) groups. RESULTS: ROC analysis revealed that MMP-3 improvement rates at 12 weeks in bio-switch patients had the highest AUC with a cut-off value of 20.0% for predicting LDA achievement at 52 weeks. Multivariate logistic regression analysis revealed that, in addition to DAS28-CRP at baseline, achieving 20% improvement in MMP-3 levels at 12 weeks was an independent predictive factor (adjusted OR: 4.277, p=0.003) in the bio-switch group, whereas DAS28 was the only predictor in the bio-naïve group. Patients who achieved 20% improvement in MMP-3 levels at 12 weeks had significantly higher achievement rates of LDA at 52 weeks compared to those who did not achieve 20% improvement in the bio-switch group (60.0 vs. 33.3%, p=0.001). CONCLUSIONS: Our findings suggest that improvement in MMP-3 levels is key to predicting the clinical efficacy of abatacept. Closer attention paid not only to major clinical indices, but also changes in MMP-3 levels, could improve our ability to optimise clinical results when treating bio-switch patients.

Clinical effectiveness and safety of additional administration of tacrolimus in rheumatoid arthritis patients with an inadequate response to abatacept: A retrospective cohort study.

OBJECTIVE: Abatacept (ABT) demonstrates good clinical efficacy and retention in rheumatoid arthritis (RA) patients. However, no rescue treatment option against inadequate response to ABT exists. Since tacrolimus (TAC) and ABT suppress T lymphocytes via different mechanisms and a combination of these agents could potentially be effective, this study aimed to examine the efficacy and safety of add-on TAC therapy in RA patients with inadequate response to ABT. METHODS: Of 550 patients treated with ABT and registered in a Japanese multicenter registry, 25 consecutive patients who underwent add-on TAC therapy and were followed for longer than 24 weeks were included in this study. RESULTS: Mean patient age was 67.0 years, disease duration was 16.2 years, and duration of ABT treatment was 1.2 years at the initiation of add-on TAC therapy. Mean TAC dose was 1.2 mg/d at baseline and 1.6 mg/d at week 24. Mean Disease Activity Score of 28 joints - erythrocyte sedimentation rate was significantly improved at week 24 (3.35) relative to baseline (4.97). The proportion of patients who achieved low disease activity or remission was 40.0%, and the European League Against Rheumatism moderate or good response was 72.0%. ABT retention rate was 92.0% at week 24, as calculated by Kaplan-Meier analysis. Only one patient discontinued add-on TAC therapy due to an adverse event (itching sensation). CONCLUSION: This is the first report describing the efficacy and safety profile of add-on TAC therapy with a focus on RA patients with inadequate response to ABT. Our findings suggest that add-on TAC therapy is a worthwhile complementary treatment option in daily clinical practice.