Impact of microsampling on toxicological evaluation in rodent safety studies.

Recently, animal welfare has been attracting worldwide attention, and implementation of 3Rs (replacement, reduction, and refinement) is prioritized in every way possible in the drug development. Microsampling, in which small amounts of blood are collected, is attracting attention in this context. ICH S3A Q&A focused on microsampling was published in November 2017 to help accelerate the application of microsampling for toxicokinetic assessment. The increased sensitivity of drug measurement apparatuses such as mass spectrometers has made it possible to measure drug concentrations with small amounts of blood samples. In this review, we summarized the reports on toxicological influence of microsampling in rodents (rats and mice) with or without drug administration or recovery period after blood collection and influences that may arise from differences in the blood sampling site or blood sampling volume. We also summarized some perspectives on further implementation of microsampling in toxicology studies. The use of microsampling in regulatory toxicology studies has gradually increased, although at a lower rate than in discovery studies. Since more animals are used in GLP toxicology studies than in discovery studies, the effect of reducing the number of animals by microsampling is expected to be greater in the toxicology studies. This report aims to promote the application of microsampling to nonclinical studies, as it is beneficial for improving animal welfare and can contribute to the 3Rs.

No Impact of Contact Between the Medial Collar of a Hydroxyapatite-Coated Triple-Tapered Stem and the Femoral Neck on Periprosthetic Bone Mineral Density.

BACKGROUND: Hydroxyapatite-coated, triple-tapered, shorter-length stems with a medial collar have been reported with good results for a few years. We investigated whether contact between the medial collar and femoral neck affects clinical outcomes and changes in bone mineral density (BMD) in patients who have this type of stem in their total hip arthroplasty construct. METHODS: This was a retrospective, single-center study involving 62 patients scheduled for unilateral total hip arthroplasty using a hydroxyapatite-coated, triple-tapered, shorter-length stem who were followed for at least 1 year postoperatively. All patients had a Dorr type B femoral canal shape. Contact between the medial collar and the femoral neck was evaluated by computed tomography at the third postoperative month, and patients were classified into 2 groups. Postoperative clinical outcomes were investigated by the Western Ontario and McMaster Universities Arthritis Index and the Japanese Orthopaedic Association scores; radiological evaluation included stem fixation, spot welds and cortical hypertrophy, postoperative 3-dimensional stem alignment, and periprosthetic BMD changes. RESULTS: There were 51 patients in the Contact + group (collar and neck contact) and 11 in the Contact-group (no contact). There were no differences between the 2 groups in the improvement of Western Ontario and McMaster Universities Arthritis Index and Japanese Orthopaedic Association scores, stem fixation, occurrence of cortical hypertrophy, or 3-dimensional stem alignment. Radiolucent lines were present in zones 3, 4, and 5 in 6 patients (12%) in the Contact + group only, who had no statistical difference between the 2 groups. Bone mineral density (BMD) decreased most in zone 7 in both groups, with no difference between the 2 groups. CONCLUSIONS: The presence or absence of contact between the medial collar and femoral neck did not affect postoperative BMD changes or radiological or clinical results. LEVEL OF EVIDENCE: Therapeutic Level III.

Relationship between body mass index and spinal pathology in community-dwelling older adults.

PURPOSE: To clarify the relationship between body mass index (BMI) and spinal pathologies including spinal sagittal balance, back extensor strength (BES), paraspinal muscle mass, prevalent vertebral fracture, disc degeneration, Modic changes, low back pain, and quality of life (QOL) in community-dwelling older adults. METHODS: This study included 380 participants (age: ≥ 65 years, male/female: 152/228) from the Shiraniwa Study. Multivariate nonlinear regression analysis was used to investigate the relationship between BMI and sagittal vertical axis (SVA), BES, paraspinal muscle mass, visual analog scale (VAS) for low back pain, Oswestry Disability Index (ODI), and EuroQoL-5 Dimension (EQ5D) score after adjusting for sex, age, Hospital Anxiety and Depression Scale score, and Charlson Comorbidity Index. In addition, multiple logistic regression analysis was used to investigate the association between BMI and prevalent vertebral fracture, disc degeneration, and Modic changes. RESULTS: BMI was significantly correlated with SVA, BES, paraspinal muscle mass, VAS, ODI, and EQ5D score. The increase in BMI was associated with the deterioration of all outcomes, which accelerated when the BMI increased from approximately 22-23 kg/m2. Moreover, overweight/obesity was significantly correlated with disc degeneration and Modic changes. CONCLUSION: Increased BMI is significantly associated with spinal pathologies such as SVA, BES, paraspinal muscle mass, VAS, QOL, disc degeneration, and Modic changes. The findings suggest that measures for controlling overweight and obesity among older adults can play an important role in the prevention and treatment of spinal pathologies.

Molecular detection of maturation stages in the developing kidney.

Recent advances in stem cell biology have enabled the generation of kidney organoids in vitro, and further maturation of these organoids is observed after experimental transplantation. However, the current organoids remain immature and their precise maturation stages are difficult to determine because of limited information on developmental stage-dependent gene expressions in the kidney in vivo. To establish relevant molecular coordinates, we performed single-cell RNA sequencing (scRNA-seq) on developing kidneys at different stages in the mouse. By selecting genes that exhibited upregulation at birth compared with embryonic day 15.5 as well as cell lineage-specific expression, we generated gene lists correlated with developmental stages in individual cell lineages. Application of these lists to transplanted embryonic kidneys revealed that most cell types, other than the collecting ducts, exhibited similar maturation to kidneys at the neonatal stage in vivo, revealing non-synchronous maturation across the cell lineages. Thus, our scRNA-seq data can serve as useful molecular coordinates to assess the maturation of developing kidneys and eventually of kidney organoids.

Building kidney organoids from pluripotent stem cells.

PURPOSE OF REVIEW: During embryogenesis, the kidney is mainly generated from three progenitor cells; nephron progenitors, ureteric bud progenitors and stromal progenitors. Mutual interactions of the all three progenitor populations are essential to form a functional kidney with the higher-order structure. Pluripotent stem cells have potential to differentiate into all cell types of the animal body, including the kidney. In this review, we will summarize recent advances in reconstructing kidney organoids from pluripotent stem cells. RECENT FINDINGS: In the past years, major advances were reported to induce nephron and ureteric bud progenitors from pluripotent stem cells in mice and humans, and to create kidney organoids of nephron and/or ureteric bud-derived collecting duct tissues in vitro. These kidney organoid technologies were applied to high-throughput genetic screenings and small chemical screenings to identify key factors for kidney development and disease. Furthermore, a novel method was established to induce stromal progenitors from pluripotent stem cells, leading to creation of kidney organoids with the higher-order structures completely derived from pluripotent stem cells. SUMMARY: These advances in kidney organoids from pluripotent stem cells should lay a foundation to establish a novel therapy for kidney disease, which ultimately eliminate the need of dialysis and kidney transplantation for patients with kidney disease in the future.

Phosphatidylcholine (18:0/20:4), a potential biomarker to predict ethionamide-induced hepatic steatosis in rats.

Ethionamide (ETH), a second-line drug for multidrug-resistant tuberculosis, is known to cause hepatic steatosis in rats and humans. To investigate predictive biomarkers for ETH-induced steatosis, we performed lipidomics analysis using plasma and liver samples collected from rats treated orally with ETH at 30 and 100 mg/kg for 14 days. The ETH-treated rats developed hepatic steatosis with Oil Red O staining-positive vacuolation in the centrilobular hepatocytes accompanied by increased hepatic contents of triglycerides (TG) and decreased plasma TG and total cholesterol levels. A multivariate analysis for lipid profiles revealed differences in each of the 35 lipid species in the plasma and liver between the control and the ETH-treated rats. Of those lipids, phosphatidylcholine (PC) (18:0/20:4) decreased dose-dependently in both the plasma and liver. Moreover, serum TG-rich very low-density lipoprotein (VLDL) levels, especially the large particle fraction of VLDL composed of PC containing arachidonic acid (20:4) involved in hepatic secretion of TG, were decreased dose-dependently. In conclusion, the decreased PC (18:0/20:4) in the liver, possibly leading to suppression of hepatic TG secretion, was considered to be involved in the pathogenesis of the ETH-induced hepatic steatosis. Therefore, plasma PC (18:0/20:4) levels are proposed as mechanism-related biomarkers for ETH-induced hepatic steatosis.

A cemented mobile-bearing total knee prosthesis prevents peri-prosthetic bone mineral density loss around the femoral component: a consecutive follow-up at a mean of 11 years.

PURPOSE: Research has shown that a cemented mobile-bearing component has a favorable effect on the bone mineral density (BMD) of the distal femur at 2 years after total knee arthroplasty (TKA). This study was performed to determine whether the advantage on BMD of a cemented mobile-bearing TKA over a conventional cemented fixed-bearing TKA changes with time. This report is an update of a matched cohort study initiated in 2004 and for which the 2-year results have been published. METHODS: Twenty-eight knees that were treated with a fixed-bearing posterior stabilized (PS) prosthesis and 28 matched knees from a database of 76 knees that were treated with a mobile-bearing PS prosthesis in the same period were investigated. All knees underwent dual-energy X-ray absorptiometry (DEXA) scans around the femoral component preoperatively, 2 weeks postoperatively, 5 years postoperatively, and annually thereafter. Eighteen knees with a cemented mobile-bearing PS prosthesis and 20 knees with a cemented fixed-bearing PS prosthesis were investigated for more than 6 years. The mean follow-up period was 11 years. RESULTS: The range of motion, Knee Society Score, BMD of the lumbar spine, and follow-up period were not significantly different preoperatively and postoperatively in the two groups. In the fixed-bearing group, the BMD of the anterior part of the femoral condyle decreased postoperatively. In the mobile-bearing group, the BMD of the posterior part of the femoral condyle increased postoperatively. The postoperative change in the BMD at 5 years and the latest follow-up period was statistically significant in the two groups. CONCLUSIONS: This DEXA study revealed that a cemented mobile-bearing component had a favorable effect on the BMD of the distal femur after TKA even at a mean of 11 years postoperatively. LEVEL OF EVIDENCE: Therapeutic study, level II, prospective comparative study.

Is medial pivot total knee arthroplasty suitable for patients with valgus knee osteoarthritis?

PURPOSE: Medial pivot total knee arthroplasty (MP-TKA) is characterized by the ball-in-socket medial tibiofemoral articulation to achieve low wear and to reproduce the medial pivot motion similar to that in the normal knee, and there have been reports of favorable long-term postsurgical outcomes. However, most of these cases concerned varus knees, and the outcomes of MP-TKA in valgus knees are unknown. The objective of this study was to investigate the postoperative outcomes in end-stage valgus knee OA patients who underwent MP-TKA, through comparisons with those who underwent TKA using the same prosthesis for varus deformity. METHODS: This retrospective, single-center, cohort study analyzed 171 knees of 121 patients who were divided into two groups (valgus knee group: 15 knees (13 patients), varus knee group: 156 knees (109 patients)). Primary outcome measures included the knee joint range of motion (evaluated preoperatively and at every year postoperatively). Secondary outcomes included operative time, laboratory data, estimated blood loss, clinical outcome measures and adverse events. RESULTS: There were no significant differences in age, sex and body mass index, as well as in the postoperative primary and secondary outcome measures between the two groups. CONCLUSION: The use of MP-TKA featuring ball-in-socket medial tibiofemoral articulation in patients with valgus knee OA showed equally favorable clinical outcomes more than 2 years after surgery, compared to patients with varus knees who received MP-TKA.

PKD1-Dependent Renal Cystogenesis in Human Induced Pluripotent Stem Cell-Derived Ureteric Bud/Collecting Duct Organoids.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease leading to renal failure, wherein multiple cysts form in renal tubules and collecting ducts derived from distinct precursors: the nephron progenitor and ureteric bud (UB), respectively. Recent progress in induced pluripotent stem cell (iPSC) biology has enabled cyst formation in nephron progenitor-derived human kidney organoids in which PKD1 or PKD2, the major causative genes for ADPKD, are deleted. However, cysts have not been generated in UB organoids, despite the prevalence of collecting duct cysts in patients with ADPKD. METHODS: CRISPR-Cas9 technology deleted PKD1 in human iPSCs and the cells induced to differentiate along pathways leading to formation of either nephron progenitor or UB organoids. Cyst formation was investigated in both types of kidney organoid derived from PKD1-deleted iPSCs and in UB organoids generated from iPSCs from a patient with ADPKD who had a missense mutation. RESULTS: Cysts formed in UB organoids with homozygous PKD1 mutations upon cAMP stimulation and, to a lesser extent, in heterozygous mutant organoids. Furthermore, UB organoids generated from iPSCs from a patient with ADPKD who had a heterozygous missense mutation developed cysts upon cAMP stimulation. CONCLUSIONS: Cysts form in PKD1 mutant UB organoids as well as in iPSCs derived from a patient with ADPKD. The organoids provide a robust model of the genesis of ADPKD.

Predictors of dropout from cohort study due to deterioration in health status, with focus on sarcopenia, locomotive syndrome, and frailty: From the Shiraniwa Elderly Cohort (Shiraniwa) study.

BACKGROUND: Conditions of the elderly like sarcopenia, locomotive syndrome, and frailty have been attracting attention recently. However, the relationship of these 3 conditions and the difference in the magnitude of influence each has on deterioration in health status remain unclear. The purpose of this study was to investigate the prevalence and relationship of sarcopenia, locomotive syndrome, and frailty, and to clarify their influence on the dropout from cohort study due to deterioration in health status. METHODS: The 1st survey of the Shiraniwa Elderly Cohort (Shiraniwa) study was conducted in 2016. We examined 409 participants (aged ≥ 65 years; 164 males, 245 females) and assessed sarcopenia, locomotive syndrome, and frailty. Those who could not attend the 2nd survey (2017) due to deterioration in health status were defined as the Dropout group. We investigated the predictors of Dropout using multiple logistic regression analysis. RESULTS: The prevalence of sarcopenia, locomotive syndrome stage 2, and frailty were 4.4%, 40.1%, and 14.2%, respectively; 89.7% of participants with frailty were also diagnosed with locomotive syndrome stage 2. From the results of the 2nd survey, 46 people were classified into the Dropout group. Independent predictors of the Dropout were locomotive syndrome stage 2 (adjusted odds ratio [OR]: 2.42, 95% confidence interval [CI]: 1.11-5.31) and frailty (adjusted OR: 3.37, 95%CI: 1.56-7.30). CONCLUSIONS: Locomotive syndrome stage 2 was the most common condition in the elderly, and most people with frailty also had locomotive syndrome stage 2. Locomotive syndrome stage 2 and frailty independently influenced the dropout from cohort study due to deterioration in health status. These results suggest that screening for locomotive syndrome is useful for early detection of the elderly with a risk of deterioration in health status, and screening for frailty may contribute to detecting the elderly with higher risk of deterioration in health status.

Changes in patient-perceived leg length discrepancy following total hip arthroplasty.

PURPOSE: Leg length discrepancy (LLD) after total hip arthroplasty (THA) prevents functional recovery and reduces patient satisfaction. We investigated impact of changes in patient-perceived LLD on patient satisfaction and walking ability. METHODS: one hundred and forty-nine patients with unilateral hip osteoarthritis undergoing THA from 2014 to 2017, (125 women, 24 men; average age, 68.5 years) with an objective LLD < 1 cm were included. Outcome measures included the patient-perceived LLD, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, 10-m walking speed, and affected leg loading rate, assessed preoperatively and at 3 weeks, 3 months, and 1 year postoperatively. RESULTS: The absolute patient-perceived LLD (mean ± SD) (the number of patients with perceived LLD > 5 mm) were 6.4 ± 9.6 mm [88 patients (59%)] preoperatively; and 2.2 ± 4.0 mm [48 (32%); p < 0.001], 0.7 ± 2.3 mm [17 (11%); p < 0.001], and 0.4 ± 1.6 mm [10 (7%); p = 0.095] at 3 weeks, 3 months, and 1 year postoperatively, respectively. All outcome measures improved over time. One year postoperatively, a weak positive correlation between the patient-perceived LLD and WOMAC or 10-m walking speed (r = 0.24, 0.23, respectively) was found. The risk of patient-perceived LLD persisting > 1 year postoperatively was 5.5-fold higher in patients who exhibited it at 3 months and those with a WOMAC score > 10 at 3 months postoperatively, using multivariate logistic regression. CONCLUSION: Achieving a post-THA objective LLD < 1 cm significantly reduced the patient-perceived LLD up to 3 months postoperatively. The residual patient-perceived LLD at 1 year postoperatively was predicted from the WOMAC score or the presence of patient-perceived LLD at 3 months after THA. LEVEL OF EVIDENCE: Therapeutic level IV.

Periprosthetic Loss of Bone Mineral Density After Cementless Porous Tantalum and Cemented Total Knee Arthroplasties: A Mean of 11-Year Concise Follow-Up of a Previous Report.

BACKGROUND: Our previous study showed that the decrease in relative change of bone mineral density (BMD) in the lateral part of the tibia was significantly less in the group treated with the cementless porous tantalum component than in the group treated with the cemented cobalt-chromium tibial component up to 5 years after the operation. However, the long-term benefits of porous tantalum tibial component on BMD have not been proven. The aim of this study was to update a matched cohort study at a minimum of 6 years' follow-up period. METHODS: Twenty patients with a porous tantalum tibial component and 18 patients with a cemented cobalt-chromium-alloy tibial component were investigated for more than 6 years in the present study. The mean follow-up period was 11.4 years. Dual X-ray absorptiometry was used to measure the BMD. RESULTS: The decrease in relative change of BMD in the lateral aspect of the tibia was significantly less with the porous tantalum tibial component than that with the cemented cobalt-chromium tibial component up to 5 years. However, at the final follow-up period, no significant difference was observed in the relative change of BMD between the 2 groups. No prosthetic migration or periprosthetic fracture was detected in either group. CONCLUSION: The present study is one of the studies with the longest follow-up period on BMD after total knee arthroplasty. Porous tantalum tibial component did not have a favorable effect on the BMD of the proximal tibia after total knee arthroplasty for long term.

Crystallographic orientation of the c-axis of biological apatite as a new index of the quality of subchondral bone in knee joint osteoarthritis.

The aim of the present study was to investigate the preferred orientation of biological apatite (BAp) as a new index of the quality of subchondral bone (SB) in knee joint osteoarthritis (OA). Ten OA and five normal knee joints were obtained. Thickness, quantity and bone mineral density (BMD) of SB were analyzed at the medial condyle of the femur in dry conditions by peripheral quantitative computed tomography. In addition, the preferred crystallographic orientation of the c-axis of BAp was evaluated as bone quality parameter using a microbeam X-ray diffractometer technique. BMD and thickness of SB were significantly increased in OA specimens compared to normal knee specimens (P < 0.01), and the preferred orientation of the c-axis of BAp along the normal direction of SB surface was significantly higher in OA specimens (P < 0.01), reflecting the change in stress of concentration in the pathological portion without cartilage. SB sclerosis in OA results in both proliferation of bone tissues and enhanced degree of preferential alignment of the c-axis of BAp. Our findings could have major implications for the diagnosis of clinical studies, including pathologic elucidation in OA.

Arachidonic acid-containing phosphatidylcholine characterized by consolidated plasma and liver lipidomics as an early onset marker for tamoxifen-induced hepatic phospholipidosis.

Lipid profiling has emerged as an effective approach to not only screen disease and drug toxicity biomarkers but also understand their underlying mechanisms of action. Tamoxifen, a widely used antiestrogenic agent for adjuvant therapy against estrogen-positive breast cancer, possesses side effects such as hepatic steatosis and phospholipidosis (PLD). In the present study, we administered tamoxifen to Sprague-Dawley rats and used lipidomics to reveal tamoxifen-induced alteration of the hepatic lipid profile and its association with the plasma lipid profile. Treatment with tamoxifen for 28 days caused hepatic PLD in rats. We compared the plasma and liver lipid profiles in treated vs. untreated rats using a multivariate analysis to determine differences between the two groups. In total, 25 plasma and 45 liver lipids were identified and altered in the tamoxifen-treated group. Of these lipids, arachidonic acid (AA)-containing phosphatidylcholines (PCs), such as PC (17:0/20:4) and PC (18:1/20:4), were commonly reduced in both plasma and liver. Conversely, tamoxifen increased other phosphoglycerolipids in the liver, such as phosphatidylethanolamine (18:1/18:1) and phosphatidylinositol (18:0/18:2). We also examined alteration of AA-containing PCs and some phosphoglycerolipids in the pre-PLD stage and found that these lipid alterations were initiated before pathological alteration in the liver. In addition, changes in plasma and liver levels of AA-containing PCs were linearly associated. Moreover, levels of free AA and mRNA levels of AA-synthesizing enzymes, such as fatty acid desaturase 1 and 2, were decreased by tamoxifen treatment. Therefore, our study demonstrated that AA-containing PCs might have potential utility as novel and predictive biomarkers for tamoxifen-induced PLD. Copyright © 2017 John Wiley & Sons, Ltd.

Differentiated kidney epithelial cells repair injured proximal tubule.

Whether kidney proximal tubule harbors a scattered population of epithelial stem cells is a major unsolved question. Lineage-tracing studies, histologic characterization, and ex vivo functional analysis results conflict. To address this controversy, we analyzed the lineage and clonal behavior of fully differentiated proximal tubule epithelial cells after injury. A CreER(T2) cassette was knocked into the sodium-dependent inorganic phosphate transporter SLC34a1 locus, which is expressed only in differentiated proximal tubule. Tamoxifen-dependent recombination was absolutely specific to proximal tubule. Clonal analysis after injury and repair showed that the bulk of labeled cells proliferate after injury with increased clone size after severe compared with mild injury. Injury to labeled proximal tubule epithelia induced expression of CD24, CD133, vimentin, and kidney-injury molecule-1, markers of putative epithelial stem cells in the human kidney. Similar results were observed in cultured proximal tubules, in which labeled clones proliferated and expressed dedifferentiation and injury markers. When mice with completely labeled kidneys were subject to injury and repair there was no dilution of fate marker despite substantial proliferation, indicating that unlabeled progenitors do not contribute to kidney repair. During nephrogenesis and early kidney growth, single proximal tubule clones expanded, suggesting that differentiated cells also contribute to tubule elongation. These findings provide no evidence for an intratubular stem-cell population, but rather indicate that terminally differentiated epithelia reexpress apparent stem-cell markers during injury-induced dedifferentiation and repair.

Local Efficacy of Periarticular Morphine Injection in Simultaneous Bilateral Total Knee Arthroplasty: A Prospective, Randomized, Double-Blind Trial.

BACKGROUND: The periarticular multimodal cocktail injection including morphine is currently commonly used to reduce postoperative pain following total knee arthroplasty (TKA). Despite its analgesic effect, it frequently causes nausea, which is an adverse effect of opioids. It is inconclusive whether the intraoperative injection of periarticular morphine is effective peripherally. The aim of this study was to assess whether the addition of morphine to unilateral periarticular knee injections improves postoperative pain, range of motion, and swelling in patients undergoing simultaneous bilateral TKA. METHODS: A prospective, single-center, double-blinded, randomized, controlled trial was conducted to assess the local efficacy of adding morphine to intraoperative periarticular anesthesia in patients undergoing simultaneous bilateral TKA. Fifty-three patients undergoing 106 TKAs received an intraoperative periarticular injection in randomly selected one knee with added morphine (0.1 mg/kg) and the other knee without added morphine. The periarticular injection was composed of ropivacaine (a local anesthetic), epinephrine, ketoprofen, and methylprednisolone sodium. Visual analog scale pain scores at rest and on motion, range of motion (ROM), thigh swelling, the Western Ontario and McMaster Universities Osteoarthritis Index score, and adverse outcomes were compared between the 2 knees. RESULTS: There were no statistically significant differences in the visual analog scale score, ROM, thigh girth, Western Ontario and McMaster Universities Osteoarthritis Index score, and adverse events between the 2 sides. CONCLUSION: Adding morphine to periarticular injections is ineffective locally for relieving pain, reducing swelling, and improving the postoperative ROM.

Effect of Periarticular Morphine Injection for Total Knee Arthroplasty: A Randomized, Double-Blind Trial.

BACKGROUND: The periarticular multimodal cocktail injection including morphine is currently commonly used to treat postoperative pain after total knee arthroplasty (TKA). Despite its analgesic effect, it is frequently reported to cause nausea and vomiting, which are adverse effects of opioids. This study aimed to assess the efficacy of morphine as a component of a multimodal cocktail injection for providing postoperative analgesia and alleviating swelling in patients who underwent TKA. METHODS: This is a prospective, single-center, randomized controlled trial involving 102 patients scheduled for unilateral TKA. A mixture of steroids, local anesthetics, nonsteroidal anti-inflammatory drugs, and epinephrine with or without morphine (10 mg) was injected to randomly assigned patients. Postoperative assessment was performed with all attending personnel and patients blinded to group assignment. Visual analog scale of pain, range of motion, nausea numerical rating scale, number of patients with vomiting, total dose of antiemetic drugs used, thigh swelling, the Western Ontario and McMaster Universities Osteoarthritis Index score, and adverse outcomes were compared between groups on postoperative days. RESULTS: Visual analog scale scores did not differ between the 2 groups at any postoperative time point. The nausea numerical rating scale scores during the postoperative period from 30 min to 9 h, the number of vomiting episodes, and the total dose of antiemetic drugs administered were significantly higher in the morphine group. The thigh girth, Western Ontario and McMaster Universities Osteoarthritis Index, and the incidence of complications were not different between groups. CONCLUSION: The results of this study suggested that addition of morphine to the multimodal cocktail injection is not effective for relieving postoperative pain, alleviating swelling, or improving range of motion, and results in nausea and vomiting.

Efficacy of the Anatomical-Pelvic-Plane Positioner in Total Hip Arthroplasty in the Lateral Decubitus Position.

BACKGROUND: Total hip arthroplasty in the lateral position involves particularly large variance in the sagittal tilt of pelvis fixation, which affects the imprecision of the cup anteversion leading to poor outcomes. We have added an additional compression pad to an existing device, also to be used in the lateral position, but theoretically enabling fixation on the anatomical pelvic plane (APP) serving as the reference plane. The present study aims to evaluate the usefulness of this device in comparison with the conventional device. METHODS: We have studied 141 patients who underwent total hip arthroplasty at our hospital. Two frontal plain x-rays of the pelvis were obtained preoperatively for each patient after pelvis fixation; one with the conventional lateral fixation device and the other with an APP lateral fixation device. The sagittal tilt of the pelvis in each position was measured with 3D templating software, and variance in the sagittal tilt was compared between the 2 devices. RESULTS: The mean bias in sagittal tilt relative to the functional pelvic plane (FPP) in the conventional device was -5.0° ± 4.8° (minus mean backward tilt) and was within 5° relative to the functional pelvic plane in 43%. The mean bias in the sagittal tilt relative to the APP in the APP lateral position device was 1.7° ± 3.1° (forward tilt) and was within 5° relative to the APP in 89%. The APP lateral device significantly reduced the variance in the sagittal tilt. CONCLUSION: This device holds promise as a means of reducing the sagittal tilt in a simple, minimally invasive, and highly cost-effective manner.

Efficacy of a Pelvic Lateral Positioner With a Mechanical Cup Navigator Based on the Anatomical Pelvic Plane in Total Hip Arthroplasty.

BACKGROUND: The acetabular component orientation in total hip arthroplasty (THA) is of critical importance to the good clinical results. However, traditional widely used cup alignment guides for cup placement are reported to be relatively unreliable. The present study aims at comparing a novel cup alignment guide, which can be attached to our anatomical pelvic plane (APP) pelvic lateral positioner for reducing discrepancies in sagittal pelvic tilt and indicate a targeted cup angle based on the APP, with a conventional cup alignment guide. METHODS: The subjects were 136 hips of 136 patients who underwent unilateral THA using the APP positioner. The procedure was performed with the conventional cup alignment guide (conventional group; 60 hips) and with the novel cup navigator (mechanical navigator group; 76 hips). Postoperative cup angles and discrepancies of postoperative cup angles (inclination and anteversion angles) from the targeted angles were compared between the 2 groups to evaluate the usefulness of these navigators. RESULTS: The mean cup angles in the conventional group were 39.0° ± 5.3° for the inclination angle and 21.7° ± 6.4° for the anteversion angle, whereas those in the mechanical navigator group were 40.6° ± 3.2° and 18.3° ± 4.6°, respectively (P = .018, P < .0001). The discrepancies from the targeted angles were 3.5° ± 3.1° for the inclination angle and 4.6° ± 3.4° for the anteversion angle in the conventional group and 2.3° ± 2.3° and 3.2° ± 2.7°, respectively, in the mechanical navigator group (P = .020, P = .012). CONCLUSION: The mechanical cup navigator easily attachable to the APP positioner is a tool that can improve the accuracy of cup placement in a simple, economical, and noninvasive manner in THA via the lateral position.

Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human-Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans.

In the development of drugs, we sometimes encounter fatty change of the hepatocytes (steatosis) which is not accompanied by degenerative change in the liver in non-clinical toxicity studies. In this study, we investigated the relationships between fatty change of the hepatocytes noted in non-clinical toxicity studies of compound X, a candidate compound in drug development, and mitochondrial dysfunction in order to estimate the potential risk of the compound to induce drug-induced liver injury (DILI) in humans. We conducted in vivo and in vitro exploratory studies for this purpose. In vivo lipidomics analysis was conducted to investigate the relationships between alteration of the hepatic lipids and mitochondrial dysfunction. In the liver of rats treated with compound X, triglycerides containing long-chain fatty acids, which are the main energy source of the mitochondria, accumulated. Accumulation of these triglycerides was considered to be related to the inhibition of mitochondrial respiration based on the results of in vitro mitochondria toxicity studies. In conclusion, fatty change of the hepatocytes (steatosis) in non-clinical toxicity studies of drug candidates can be regarded as a critical finding for the estimation of their potential risk to induce DILI in humans when the fatty change is induced by mitochondrial dysfunction.