Correlation between magnesium pre-loading and cisplatin-induced nephrotoxicity in 5-fluorouracil/cisplatin combination therapy for esophageal cancer.

The use of cisplatin may cause nephrotoxicity in patients. Hydration solutions supplemented with magnesium could reduce cisplatin-induced nephrotoxicity. In this study, we evaluated the preventive effect of magnesium pre-loading on cisplatin-induced nephrotoxicity in patients with esophageal cancer. We retrospectively evaluated the prevalence of, and risk factors for, nephrotoxicity in 160 patients with esophageal cancer treated with the 5-fluorouracil/cisplatin regimen from 2014 to 2016 with and without magnesium supplementation. Significant differences were observed between the magnesium and non-magnesium groups in terms of frequency of estimated creatinine clearance of grade 2 or higher that was at 4% (n = 3) and 13% (n = 10) (p = 0.027), respectively. The logistic regression analysis revealed that eCcr of grade 2 or higher was significantly associated with the non-magnesium regimen (odds ratio (OR), 4.175; 95% confidence interval (CI) = 1.061-16.430; p = 0.041) and age ≥ 65 years (OR, 13.951; 95% CI = 1.723-112.974; p = 0.014). This study suggests that 20 mEq magnesium pre-loading significantly reduces the prevalence of cisplatin-induced nephrotoxicity. Furthermore, when cisplatin is administered to individuals older than 64 years, a close observation for the onset of cisplatin-induced nephrotoxicity is crucial.

Load distribution and forearm muscle activity during cylinder grip at various grip strength values.

This study aimed to investigate load distribution and forearm muscle activity from strong to weak grip strength, using a cylindrical device (Grip Sensor). We invited 15 students and measured the pressure distribution and forearm muscle activity during grip tasks at 25%, 50%, 75%, and 100% maximum voluntary force (MVF). Pressure data from the Grip Sensor were assigned to seven anatomical regions; the sum of the data from the seven regions (Total force) and proportionate load distribution for each grip task were calculated. Electromyography recorded activity in the extensor carpi radialis longus (ECRL), flexor carpi radialis (FCR), extensor carpi ulnaris (ECU) and flexor carpi ulnaris (FCU) muscles. Forearm muscle activity increased significantly with grip strength (p < 0.05). The load proportion corresponding to the thumb did not significantly change with increasing strength. On the other hand, the fingertip ratio significantly decreased, and the palm ratio significantly increased with increasing strength (p < 0.05). The Grip Sensor showed a shift in the load distribution in the hand from fingertips to palm as grip strength increased. This result indicates that more detailed evaluations of hand function may be possible.

Trunk movement asymmetry associated with pain, disability, and quadriceps strength asymmetry in individuals with knee osteoarthritis: a cross-sectional study.

OBJECTIVE: This study examined 1) the clinical relevance of trunk movement asymmetry, which was evaluated using a trunk-mounted inertial measurement unit (IMU), and 2) the relationship between trunk movement asymmetry and lower limb muscle strength asymmetry in individuals with knee osteoarthritis (OA). DESIGN: One-hundred-thirty-one participants (mean age, 74.2 years; 71.8% female; Kellgren and Lawrence [K&L] grade ≥1) underwent gait analysis at their preferred pace for IMU-based measurement of trunk movement asymmetry (harmonic ratio [HR] and improved HR). The isometric strength of quadriceps and hip abductors was evaluated using a hand-held dynamometer. Pain and disability level were evaluated using a validated self-reported questionnaire. Multiple regression analyses with covariate adjustment were performed to examine the relationship between trunk movement asymmetry (independent variable) and pain, disability level, or muscle strength asymmetry (dependent variables). RESULTS: Individuals with severe knee OA (K&L grade ≥3) had increased trunk movement asymmetry in the medio-lateral axis compared to those with a K&L grade of 1. Increased trunk movement asymmetry was associated with a greater knee pain and disability. The increased trunk movement asymmetry was significantly associated with an increase in the asymmetry of quadriceps strength, but not with asymmetry in the strength of hip abductor. CONCLUSION: Our findings indicate that increased medio-lateral trunk movement asymmetry may be an indicator of impairment, rather than adaptation, in individuals with knee OA. This preliminary finding warrants validation by future study. Paying close attention to medio-lateral trunk movement asymmetry may be key to our understanding of OA-related pain and disability.

Interaction between low back pain and knee pain contributes to disability level in individuals with knee osteoarthritis: a cross-sectional study.

OBJECTIVE: To test the hypothesis that the interaction between low back pain (LBP) and knee pain intensity contributes to the disability level of individuals with knee osteoarthritis (OA). DESIGN: Community-dwelling participants with knee OA (Kellgren/Lawrence [K/L] grade ≥1) were enrolled. LBP and its severity were identified using questionnaires. Knee pain severity and disability level were evaluated using the Japanese Knee Osteoarthritis Measure (JKOM) subscale. Multiple linear regression analyses were performed to examine the effect of the LBP-knee pain interaction, an independent variable, on disability, a dependent variable. RESULTS: A total of 260 participants (age, 48-88 years; 77.7% women) were included. Of them, 151 (58.1%) had LBP. The LBP-knee pain interaction was significantly associated with disability after the adjustment for covariates. A post-hoc subgroup analysis revealed that the relationship between knee pain intensity and disability level was higher in individuals with LBP (beta: 0.621 points; 95% confidence interval [CI]: 0.511 to 0.731 points) than in those without LBP (beta: 0.402 points; 95% CI: 0.316 to 0.487 points). CONCLUSIONS: LBP interacts with knee pain intensity and contributes to disability level in individuals with knee OA. Coexisting LBP and knee pain had a stronger impact on disability level than LBP or knee pain alone. These findings highlight the potential deteriorative effects of the LBP-knee interaction on disability. Maximal treatment effects for disability might be achieved when LBP and knee pain are targeted simultaneously, rather than separately.

Lack of ethnic differences of moxifloxacin and metabolite pharmacokinetics in East Asian men.

This study was designed to investigate ethnic differences in the pharmacokinetics (PKs) of moxifloxacin and its metabolites, M1 (sulfo conjugate) and M2 (acyl-glucuronate), among Japanese, Chinese, and Korean populations, following oral administration. We used a population PK modeling approach using data from a clinical study involving 79 healthy male volunteers. A comprehensive population PK model considering the PK mechanism of moxifloxacin and its metabolites was newly built. The structures of the final model were two-compartment for moxifloxacin and one-compartment for M1 and M2, with first-order absorption with lag time for all three compounds. The formation of M1 and M2 from moxifloxacin via a first-pass effect and subsequent metabolic clearance in the system were also modeled. Lean body mass on the central volume of distribution (V c ) and estimated glomerular filtration rate on renal clearance (CL r ) were identified as covariates of PKs of moxifloxacin. Additionally, bioavailability was slightly higher in Koreans, whereas CL r , non-renal clearance (CL nr ), and V c were slightly lower. Regarding M1 and M2, body surface area on CL r of M2 and UGT1A1*6 on F of M2 were modeled. Korean ethnicity was observed to influence CL nr of M2, F of M2, and the metabolic clearance of moxifloxacin to M2. However, the exposure levels of moxifloxacin, M1, and M2 in Koreans were comparable to those in Japanese and Chinese because the effects of Korean ethnicity on some PK parameters were counterbalanced. These results suggest that PKs for moxifloxacin and its metabolites among East Asian populations are essentially similar.

A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer.

BACKGROUND: The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naïve patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach. PATIENTS AND METHODS: Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0-1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out. RESULTS: Overall, 361 patients were randomized (S-1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1-20; 5-FU/cisplatin: 1-30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had ≥1 grade 3/4 treatment-emergent adverse event or ≥1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination. CONCLUSIONS: These data suggest that S-1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in untreated patients with advanced diffuse adenocarcinoma of the gastroesophageal junction or stomach. The primary end point was not met. CLINICALTRIAL.GOV REGISTRATION NUMBER: NCT01285557.

Early results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 and docetaxel/cisplatin/S-1 as neoadjuvant chemotherapy for locally advanced gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is a promising method of improving the survival of resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both effective against metastatic gastric cancer. This report clarified the impact of these regimens on early endpoints, including the pathological responses, chemotherapy-related toxicities, and surgical results. METHODS: Patients with M0 and either T4 or T3 in case of junctional cancer or scirrhous type received two or four courses of cisplatin (60 mg/m2 at day 8)/S-1 (80 mg/m2 for 21 days with 1 week rest) or docetaxel (40 mg/m2 at day 1)/cisplatin (60 mg/m2 at day 1)/S-1 (80 mg/m2 for 14 days with 2 weeks rest) as NAC. Patients then underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was the 3-year overall survival. RESULTS: Between October 2011 and September 2014, 132 patients were assigned to receive CS (n = 66; 33 in 2 courses and 33 in 4 courses) or DCS (n = 66; 33 in 2 courses and 33 in 4 courses). The respective major grade 3 or 4 hematological toxicities (CS/DCS) were leukocytopenia (14.1%/26.2%), neutropenia (29.7%/47.7%), anemia (14.1%/12.3%), and platelet reduction (3.1%/1.5%). The rate of pathological response, defined as a complete response or < 10% residual cancer remaining, was 19.4% in the CS group and 15.4% in the DCS group, and 15.6% in the two-course group and 19.0% in the 4-course group. The R0 resection rate was 72.7% in the CS group and 81.8% in the DCS group and 80.3% in the two-course group and the 74.2% in the four-course group. No treatment-related deaths were observed. CONCLUSIONS: Our results do not support three-drug therapy with a taxane over two-drug therapy, or any further treatment beyond two cycles as an attractive candidate for the test arm of NAC.

Coexisting lateral tibiofemoral osteoarthritis is associated with worse knee pain in patients with mild medial osteoarthritis.

OBJECTIVE: To examine the clinical impact of coexisting lateral osteoarthritis (OA) in knees with mild medial OA. DESIGN: In patients with Kellgren/Lawrence (K/L) grade 2 OA in the medial compartment (n = 100; age: 56-89 years; 80.0% female), anteroposterior knee radiography was used to assess the presence of lateral OA, using grading systems from the Osteoarthritis Research Society International (OARSI) atlas and the K/L classification. The Japanese Knee Osteoarthritis Measure (JKOM), knee range of motion (ROM), and performance-based functional measures (10 m walk, timed up and go and five repetition chair stand maneuvers) were evaluated. The outcomes were compared between patients with and without lateral OA using an analysis of covariance (ANCOVA) or nonparametric rank ANCOVA. Furthermore, ordinal logistic regression analysis was performed, with responses on individual JKOM pain questionnaires as the outcomes and lateral OA as the predictor. RESULTS: Knees with coexisting lateral OA had a significantly worse score of JKOM pain question compared with those without, after adjusting for covariates. The presence of lateral OA was significantly associated with knee pain while ascending/descending stairs and standing. These results were consistent between different definitions of the K/L and OARSI grading systems. The knee ROM and performance-based functional measures were not significantly different between patients with and without lateral OA. CONCLUSION: Knees with concomitant lateral and mild medial OA may be more symptomatic compared to those without lateral OA. These findings might help to define a clinically distinct subgroup based on a simple radiographic finding in mild knee OA.

Randomized clinical trial comparing standard diet with perioperative oral immunonutrition in total gastrectomy for gastric cancer.

BACKGROUND: Total gastrectomy for gastric cancer is associated with excessive weight loss and decreased calorie intake. Nutritional support using eicosapentaenoic acid modulates immune function and limits catabolism in patients with advanced cancer, but its impact in the perioperative period is unclear. METHODS: This was a randomized phase III clinical trial of addition of eicosapentaenoic acid-rich nutrition to a standard diet in patients having total gastrectomy for gastric cancer. Patients were randomized to either a standard diet or standard diet with oral supplementation of an eicosapentaenoic acid (ProSure®), comprising 600 kcal with 2·2 g eicosapentaenoic acid, for 7 days before and 21 days after surgery. The primary endpoint was percentage bodyweight loss at 1 and 3 months after surgery. RESULTS: Of 127 eligible patients, 126 were randomized; 124 patients (61 standard diet, 63 supplemented diet) were analysed for safety and 123 (60 standard diet, 63 supplemented diet) for efficacy. Across both groups, all but three patients underwent total gastrectomy with Roux-en-Y reconstruction. Background factors were well balanced between the groups. Median compliance with the supplement in the immunonutrition group was 100 per cent before and 54 per cent after surgery. The surgical morbidity rate was 13 per cent in patients who received a standard diet and 14 per cent among those with a supplemented diet. Median bodyweight loss at 1 month after gastrectomy was 8·7 per cent without dietary supplementation and 8·5 per cent with eicosapentaenoic acid enrichment (P = 0·818, adjusted P = 1·000). Similarly, there was no difference between groups in percentage bodyweight loss at 3 months (P = 0·529, adjusted P = 1·000). CONCLUSION: Immunonutrition based on an eicosapentaenoic acid-enriched oral diet did not reduce bodyweight loss after total gastrectomy for gastric cancer compared with a standard diet. Registration number: UMIN000006380 ( http://www.umin.ac.jp/).

Physiological exercise loading suppresses post-traumatic osteoarthritis progression via an increase in bone morphogenetic proteins expression in an experimental rat knee model.

OBJECTIVE: To evaluate the dose-response relationship of exercise loading in the cartilage-subchondral bone (SB) unit in surgically-induced post-traumatic osteoarthritis (PTOA) of the knee. DESIGN: Destabilized medial meniscus (DMM) surgery was performed on the right knee of 12-week-old male Wistar rats, and sham surgery was performed on the contralateral knee. Four weeks after the surgery, the animals were subjected to moderate (12 m/min) or intense (21 m/min) treadmill exercises for 30 min/day, 5 days/week for 4 weeks. PTOA development in articular cartilage and SB was examined using histological and immunohistochemical analyses, micro-computed tomography (micro-CT) analysis, and biomechanical testing at 8 weeks after surgery. Gremlin-1 was injected to determine the role of bone morphogenetic protein (BMP) signaling on PTOA development following moderate exercise. RESULTS: Moderate exercise increased BMP-2, BMP-4, BMP-6, BMP receptor 2, pSmad-5, and inhibitor of DNA binding protein-1 expression in the superficial zone chondrocytes and suppressed cartilage degeneration, osteophyte growth, SB damage, and osteoclast-mediated SB resorption. However, intense exercise had little effect on BMP expression and even caused progression of these osteoarthritis (OA) changes. Gremlin-1 injection following moderate exercise caused progression of the PTOA development down to the level of the non-exercise DMM-operated knee. CONCLUSIONS: Exercise regulated cartilage-SB PTOA development in DMM-operated knees in a dose-dependent manner. Our findings shed light on the important role of BMP expression in superficial zone chondrocytes in attenuation of PTOA development following physiological exercise loading. Further studies to support a mechanism by which BMPs would be beneficial in preventing PTOA progression are warranted.

Semi-mechanistic autoinduction model of midazolam in critically ill patients: population pharmacokinetic analysis.

WHAT IS KNOWN AND OBJECTIVE: Midazolam (MDZ) is commonly used for sedating critically ill patients. The daily dose required for adequate sedation increases in increments over 100 h after administration. The objectives of this study were to characterize the MDZ pharmacokinetics in critically ill patients and to describe the phenomenon of increasing daily dose by means of population pharmacokinetic analysis. METHODS: Data were obtained from 30 patients treated in an intensive care unit. The patients received MDZ intravenously as a combination of bolus and continuous infusion. Serum MDZ concentration was assayed by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using the NONMEM software package. The alteration of clearance unexplained by demographic factors and clinical laboratory data was described as an autoinduction of MDZ clearance using a semi-mechanistic pharmacokinetic-enzyme turnover model. RESULTS AND DISCUSSION: The final population pharmacokinetic model was a one-compartment model estimated by incorporating a semi-mechanistic pharmacokinetic-enzyme turnover model for clearance, taking autoinduction into account. A significant covariate for MDZ clearance was total bilirubin. An increase in total bilirubin indicated a reduction in MDZ clearance. From simulation using the population pharmacokinetic parameters obtained in this study, MDZ clearance increased 2·3 times compared with pre-induced clearance 100 h after the start of 12·5 mg/h continuous infusion. WHAT IS NEW AND CONCLUSION: Autoinduction and total bilirubin were significant predictors of the clearance of MDZ in this population. Step-by-step dosage adjustment using this population pharmacokinetic model may be useful for establishing a MDZ dosage regimen in critically ill patients.

The relationship between the daily step counts and low back pain during pregnancy.

PURPOSE: To investigate the relationship between the change of daily step counts and low back pain (LBP) during pregnancy. Materials and METHODS: Pregnant women at less than eight weeks of gestation (WG) were recruited. Daily step counts were measured with a pedometer. To assess LBP, the Oswestry disability index (ODI) score was recorded. Thirty-six individuals were divided into the LBP and non-LBP groups. The effect of step counts on LBP between the two groups was analyzed. RESULTS: At 16-19 WG, step counts were not considerably changed in the non-LBP group but were significantly increased in the LBP group. At 24-27 and 32-35 WG, step counts were increased in the non-LBP group but were significantly decreased in the LBP group. CONCLUSIONS: Acute increase of daily step counts in early pregnancy is a risk for LBP, and gradual increases of step counts after mid-pregnancy is recommended for women.

Exercise intervention increases expression of bone morphogenetic proteins and prevents the progression of cartilage-subchondral bone lesions in a post-traumatic rat knee model.

OBJECTIVE: This study aimed to determine whether treadmill walking (TW) prevents the progression of post-traumatic osteoarthritic changes in cartilage-subchondral bone unit, and whether the exercise timing changes the exercise efficacy in destabilized medial meniscus (DMM) rat knees. DESIGN: Twelve-week-old male Wistar rats underwent DMM surgery on their right knees and sham surgery on their left knees and were assigned to either the sedentary (n = 10) or walking (n = 24) groups. The rats in the walking group were subjected to TW from day 2 through 4 weeks, from 4 through 8 weeks, or from day 2 through 8 weeks (n = 8 per group). Osteoarthritic changes of cartilage and subchondral bone were assessed with micro-computed tomography, histology, and immunohistochemistry 8 weeks after surgery. RESULTS: TW prevented the progression of cartilage and subchondral bone lesions induced by the DMM, and increased bone morphogenetic protein (BMP)-2 and -6 expressions in superficial zone chondrocytes and bone-lining cells including osteoblasts. Furthermore, the TW-induced increase in BMPs varied with the exercise timing. Beginning TW 4 weeks after DMM surgery was the best option for increasing BMPs, coinciding with the most robust prevention of osteoarthritic changes. CONCLUSIONS: TW increased the expression of BMPs and prevented the progression of cartilage-subchondral bone lesions in rat knees with a DMM. Selective exercise timing may be a key factor in the development of an exercise regimen for preventing the progression of post-traumatic osteoarthritis (PTOA). Furthermore, exercise may have favorable effects even after the PTOA has been developed.

Rat Articular Cartilages Change Their Tissue and Protein Compositions During Perinatal Period.

Articular cartilage (AC) covers the surface of bones in joints and functions as a cushion against mechanical loading. The tissue contains abundant extracellular matrix (ECM), which mainly consists of proteoglycans (PG) and collagen (COL) fibres. The property of AC is gradually changing by ageing with gravity loading. To know the property change of AC by initial gravity loading during short period after birth, we performed histological assays and proteomics assay on the AC of the femoral condyle in knee joints of perinatal rats. The water content (%) was significantly decreased in neonate AC compared with fetal AC. During the perinatal stages (E19 and P0), the localizations of glycosaminoglycan (GAG) and type I and II COLs were homogeneous. The density of chondrocytes was significantly decreased in the deeper layers comparing with the surface layer in neonate AC. In addition, we found a drastic change in the protein expression pattern on proteomic analysis. The expressions of ECM components were relatively increased in neonate AC compared with fetal AC.

Self-assessment of Rheumatoid Arthritis Disease Activity Using a Smartphone Application. Development and 3-month Feasibility Study.

INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Methodologies, Models and Algorithms for Patients Rehabilitation". BACKGROUND: Rheumatoid arthritis (RA) is a progressive inflammatory disease that causes damage to multiple joints, decline in functional status, and premature mortality. Thus, effective and frequent objective assessments are necessary. Then, we developed a self-assessment system for RA patients based on a smartphone application. OBJECTIVE: The purpose of this study was to investigate the feasibility of a self-assessment system for RA patients using a smartphone application. METHODS: We measured daily disease activity in nine RA patients who used the smartphone application for a period of three months. A disease activity score (DAS28) predictive model was used and feedback comments relating to disease activity were shown to patients via the smartphone application each day. To assess participants' RA disease activity, the DAS28 based on the C-reactive protein level was measured by a rheumatologist during monthly clinical visits. RESULTS: The disease activity measured by the application correlated well with the patients' actual disease activity during the 3-month period, as assessed by clinical examination. Furthermore, most participants gave favourable responses to a questionnaire administered at the end of the 3-month period containing questions relating to the ease of use and usefulness of the system. CONCLUSIONS: The results of this feasibility study indicated that the DAS28 predictive model can longitudinally predict DAS28 and may be an acceptable and useful tool for assessment of RA disease activity for both patients and healthcare providers.

Subchondral plate porosity colocalizes with the point of mechanical load during ambulation in a rat knee model of post-traumatic osteoarthritis.

OBJECTIVE: This study investigated the association between spatiotemporal cartilage-subchondral bone plate alterations and mechanical load during ambulation in an experimental rat model of destabilized medial meniscus (DMM). DESIGN: Twelve-week-old Wistar rats (n = 38) underwent DMM surgery on the right knee and sham surgery on the left knee. At 2 and 4 weeks after surgery, subchondral bone changes were evaluated via micro-computed tomography with various knee flexion angles to simulate weight-bearing during rat ambulation under a 3-dimensional motion capture apparatus. Additionally, the biomechanical properties, histology, and ultrastructure of the medial tibia and femoral condyle were evaluated. RESULTS: Focal subchondral bone plate perforations were confirmed in the medial tibia within 2 weeks after surgery and were aggravated rapidly 2 weeks later. This subchondral plate porosity colocalized with articular cartilage lesions as confirmed by histology and scanning electron microscopy, and coincided with the likely point of contact between the posterior femoral condyle and tibial plateau during ambulation. Biomechanical properties were confirmed at the medial tibia, at which stiffness was reduced to approximately half that of the sham-operated knee at 4 weeks after surgery. CONCLUSIONS: Cartilage-subchondral bone plate alterations localized in the region of the point of mechanical load during ambulation in DMM-operated knees, at which the mechanical integrity of cartilage was impaired. These results indicate that DMM-induced increases in mechanical load play an important role in the pathogenesis of early post-traumatic osteoarthritis (OA), and it might accelerate the development of the disease via cartilage-subchondral bone plate crosstalk through increased subchondral plate perforations.

Analysis of factors affecting time in therapeutic range control after warfarin administration.

The protective efficacy of warfarin for cardiogenic cerebral embolism has been established. However, warfarin is generally administered to only approximately 35% of the atrial fibrillation patients who required warfarin therapy. It has been reported that international normalized ratio (INR) control was carried out appropriately in < 50% of such patients. Therefore, from the viewpoint of prevention of the onset and recurrence of embolism, the maintenance of a stable anticoagulant level is necessary. In warfarin therapy, in addition to INR control, time in therapeutic range (TTR) also markedly affects the efficacy of warfarin therapy. Therefore, we classified patients into two groups on the basis of the cutoff TTR ≥ 65% at which the inhibitory effect of warfarin on stroke has been observed. We aimed to examine the association between INR and TTR with the correction of the therapeutic efficacy of warfarin by analyzing the factors leading to poor TTR control. The most valuable finding of this study is that marked fluctuations of brain natriuretic peptide levels in patients with complication of heart failure was a risk factor for poor TTR control. Identification of the factors leading to the poor TTR control is useful for making the decision to switch to other anticoagulants, such as dabigatran or apixaban, or to continue warfarin by correcting risk factors in atrial fibrillation patients receiving long-term warfarin therapy.

Effects of short-term gentle treadmill walking on subchondral bone in a rat model of instability-induced osteoarthritis.

OBJECTIVE: Subchondral bone cyst (SBC) growth, caused by osteoclast activity during early knee osteoarthritis (OA) pathogenesis, should be treated to prevent further progressions of OA. In the present study, we evaluated the effects of gentle treadmill walking on subchondral bone and cartilage changes in an experimental rat model of destabilized medial meniscus (DMM). METHOD: Twelve-week-old Wistar rats underwent DMM surgery in their right knee and sham surgery in their left knee and were assigned to either the sedentary group or walking group (n = 42/group). Animals in the walking group were subjected to treadmill exercise 2 days after surgery, which included walking for 12 m/min, 30 min/day, 5 days/week for 1, 2, and 4 week(s). Subchondral bone and cartilage changes were evaluated by micro-CT analysis, histological analysis, and biomechanical analysis. RESULTS: Treadmill walking had a tendency to suppress SBC growth, which was confirmed by micro-CT (P = 0.06) and positive staining for tartrate-resistant acid phosphatase (TRAP) activity for the osteoclast number per bone surface (P = 0.09) 4 weeks after surgery. These changes coincide with the prevention of cartilage degeneration as evaluated by the Osteoarthritis Research Society International (OARSI) score (P < 0.05) and biomechanically softening (P < 0.05). Furthermore, treadmill walking could suppressed increasing osteocyte deaths (P < 0.01), which was positively correlated with the OARSI score (r = 0.77; P < 0.01). CONCLUSION: These results indicate biomechanical and biological links exist between cartilage and subchondral bone; preventive effects of treadmill walking on subchondral bone deterioration might be partly explained by the chondroprotective effects.