Dupuytren's contracture-associated SNPs increase SFRP4 expression in non-immune cells including fibroblasts to enhance inflammation development.

Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two single nucleotide polymorphisms (SNPs) associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and ßTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC.

Identification of small-sized intrachromosomal segments at the ends of INV-DUP-DEL patterns.

The mechanism of chromosomal rearrangement associated with inverted-duplication-deletion (INV-DUP-DEL) pattern formation has been investigated by many researchers, and several possible mechanisms have been proposed. Currently, fold-back and subsequent dicentric chromosome formation has been established as non-recurrent INV-DUP-DEL pattern formation mechanisms. In the present study, we analyzed the breakpoint junctions of INV-DUP-DEL patterns in five patients using long-read whole-genome sequencing and detected 2.2-6.1 kb copy-neutral regions in all five patients. At the end of the INV-DUP-DEL, two patients exhibited chromosomal translocations, which are recognized as telomere capture, and one patient showed direct telomere healing. The remaining two patients had additional small-sized intrachromosomal segments at the end of the derivative chromosomes. These findings have not been previously reported but they may only be explained by the presence of telomere capture breakage. Further investigations are required to better understand the mechanisms underlying this finding.

Patient factors impacting localization of popliteal artery before total knee arthroplasty.

PURPOSE: Intraoperative injury to the popliteal artery (PA) should be avoided during total knee arthroplasty (TKA). This study was performed to clarify the preoperative localization of the PA and the patient factors that impact its localization as a preventive measure. METHODS: Ninety-seven patients (110 knees; 18 men, 79 women) with osteoarthritis who underwent primary TKA were retrospectively reviewed. Preoperative sagittal magnetic resonance imaging was used to measure the distance between the PA and the closest point at three levels: the femoral epicondyle (DPF), the tibial articular surface (DPAS), and the posterior tibial cortex (DPT). All variables are expressed in millimeters as median (interquartile range). RESULTS: The median distance was 10.35 (7.90-12.34) mm for DPF, 6.32 (5.12-8.57) mm for DPAS, and 3.76 (2.28-5.26) mm for DPT. Body height and weight showed weak correlations with DPF (r = 0.324, p < 0.001 and r = 0.207, p = 0.03, respectively). DPF was smaller in women [9.82 (7.64-12.23) mm] than in men [11.27 (10.26-12.75) mm] (p = 0.004). A larger flexion angle and range of motion showed a weak negative correlation with DPT (r = - 0.282, p = 0.003 and r = - 0.236, p = 0.016, respectively). Multiple regression analysis revealed that DPF was related to body height (ß = 0.341, p < 0.001) and that DPT was related to the flexion angle (ß = - 0.264, p = 0.005). CONCLUSIONS: Special attention should be paid to women with a small physique on the femoral side and/or patients with a large flexion angle on the tibial side as a strategy to prevent PA-related complications.

Positive effect of total knee arthroplasty on progression of arteriosclerosis evaluated by cardio-ankle vascular index.

INTRODUCTION: Physical function is expected to improve with an increase in physical activity owing to improvement in knee joint pain after total knee arthroplasty (TKA). This study was performed to evaluate the impact of TKA on arteriosclerosis by measuring the cardio-ankle vascular index (CAVI) before and after surgery. MATERIALS AND METHODS: In total, 206 consecutive patients undergoing unilateral TKA were investigated. The CAVI, an index of the overall stiffness of the artery from the origin of the aorta to the ankle, was used to evaluate the degree of arteriosclerosis. The CAVI of the TKA side and non-TKA side was compared before and 1 year after TKA. RESULTS: There were no differences in the CAVI before and after TKA on the TKA side and non-TKA side, although these values should have worsened at 1 year compared with preoperative values. The CAVI, which did not differ between the two sides preoperatively, differed significantly between the two sides postoperatively (p = 0.013). A generalized linear model showed no interaction between each time point and the measured sides in terms of the CAVI. The relationship between the preoperative CAVI and the difference between the preoperative and postoperative CAVI were examined, showing that R = - 0.428 (p < 0.001) for the TKA side and R = - 0.416 (p < 0.001) for the non-TKA side (significant negative correlation). CONCLUSIONS: The lack of significant age-related deterioration over time on both sides suggests that TKA may slow the progression of arteriosclerosis, especially on the operated side. The effect of TKA was found to be greater with a higher CAVI (i.e., more advanced arteriosclerosis).

Characteristics of hidden blood loss following hybrid total knee arthroplasty.

BACKGROUND: Hidden blood loss (HBL) unrecognized by the usual practice of assessing intraoperative loss and postoperative drainage comprises a considerable proportion of total blood loss (TBL) during primary total knee arthroplasty (TKA). However, HBL has not been adequately investigated in hybrid TKA (uncemented femur, cemented tibia). The purpose of this study was to clarify the amount and influential factors of HBL in hybrid TKA. METHODS: A consecutive series of 151 knees in 137 patients with knee osteoarthritis who underwent hybrid TKA were retrospectively evaluated. We examined the correlations between HBL and various factors of concern for their effects on TBL, including age, sex, body weight (BW), body height, body mass index, operation time, tourniquet time, and visible blood loss (VBL) in three periods (intraoperative: VBL1; until 3 h postoperatively: VBL2; from 3 h to 1 day postoperatively: VBL3). RESULTS: Median (interquartile range) HBL and TBL were 528 (388, 711) mL and 725 (582, 926) mL, respectively. HBL relative to TBL (H/T) was 73%. There were weak correlations between HBL and BW (r = 0.249, p = 0.002) and between HBL and VBL3 (r = -0.261, p = 0.001). Multivariate analyses confirmed a positive correlation between HBL and BW (ß = 0.296, p < 0.001) and a negative correlation between HBL and VBL3 (ß = -0.270, p < 0.001). CONCLUSIONS: Hybrid TKA showed comparable values of HBL and H/T to those reported for cemented TKA. Therefore, management strategies for HBL in hybrid TKA can follow the same protocols used for cemented TKA. High BW and low VBL3 may be predictors of postoperative HBL in hybrid TKA.

Utilization effect of floor plan sketches in hypothetical cases assuming a community care meeting.

Objective　Floor plan sketches (FPSs) are schematic representations of floors in a home. FPSs display information gathered from observations and interviews on people's way of dwelling. To elucidate the effects of utilizing FPSs in case reviews assuming a community care meeting attended by multidisciplinary professionals, we conducted reviews of hypothetical cases created for experimental purposes.Methods　Two hypothetical cases (Cases 1 and 2) were developed, and each case was reviewed with and without FPSs. Two groups (Groups A and B) were created, each consisting of five health care and welfare professionals involved in actual case reviews. Group A reviewed Case 1 without FPSs followed by Case 2 with FPSs, while Group B reviewed Case 2 without FPSs followed by Case 1 with FPSs. Case conferences and group interviews conducted after the completion of these reviews. Based on the verbatim transcripts of the reviews and interviews, we investigated differences between case reviews with and without FPSs with regard to the time required for the review and the number and contents of participants' comments.Results　Review content could largely be divided into two categories: (1) the living conditions and support for the case subjects and their families, and (2) their homes and their way of dwelling at home. These categories were common to case reviews both with and without FPSs. In discussions about the homes and ways of dwelling, however, confirmation of the locations of rooms consumed a large amount of time in case reviews without FPSs. In case reviews with FPSs, discussions were more specific and included details such as room usage and paths by which residents move. The mean time required for a review was 41 minutes per case (range: 36 to 44 minutes), which did not greatly differ based on whether or not FPSs were used. Participants made more comments and seemed to interact more actively with each other when they had the FPSs than when they did not. The impressions of participants were that FPSs allowed the visualization of the case subjects and their families in their homes and fostered a greater feeling of familiarity with the case.Conclusion　The use of FPSs in case reviews reduces the time spent on information sharing and allows more detailed review contents. Furthermore, FPSs enhance the ability to imagine the daily lives of case subjects and their families, thereby potentially broadening assessments in case reviews.

Elevated Urinary Levels of 8-Hydroxy-2'-deoxyguanosine in a Japanese Child of Xeroderma Pigmentosum/Cockayne Syndrome Complex with Infantile Onset of Nephrotic Syndrome.

Nucleotide excision repair (NER) is an essential biological pathway protecting against ultraviolet light-induced DNA damage. Deficient NER causes a group of rare genetic disorders including two autosomal recessive diseases, xeroderma pigmentosum (XP) and Cockayne syndrome (CS). In addition to the cutaneous photosensitivity shared in XP and CS, CS is featured by growth failure, neurological deterioration, microcephaly, and deep sunken eyes. XP/CS complex is an extremely rare type of NER disorder with a distinct phenotype that is characterized by the skin and eye pathology of XP and the somatic and neurological abnormalities of CS. Some of CS cases have been reported to be complicated with renal failure, but the genetic background or the etiology of the renal failure has not been reported. We herein report a 1-year-old Japanese boy with XP/CS complex, complicated by nephrotic syndrome. Diagnosis was confirmed by the presence of compound heterozygous mutations, G47R (c.139G>A) and R616G (c.1846C>G), in the excision repair cross-complementation group 2 (ERCC2) gene. The kidney biopsies, performed at the age of 1 year and 2 months, revealed diffuse expansion of the mesangial matrix and segmental glomerulosclerosis under light microscopy, and diffused thin capillary walls with partially lamellated regions under electron microscopy. Notably, high levels of urinary 8-hydroxy-2'-deoxyguanosin, known as an oxidative stress marker, were observed during the clinical course. The patient died at the age of 1 year and 11 months because of renal failure. We suggest the involvement of oxidative stress in the pathogenesis of nephrotic syndrome in NER disorders.

Elevation of Serum Acid Sphingomyelinase Activity in Acute Kawasaki Disease.

Kawasaki disease (KD) is an acute systemic vasculitis that affects both small and medium-sized vessels including the coronary arteries in infants and children. Acid sphingomyelinase (ASM) is a lysosomal glycoprotein that hydrolyzes sphingomyelin to ceramide, a lipid, that functions as a second messenger in the regulation of cell functions. ASM activation has been implicated in numerous cellular stress responses and is associated with cellular ASM secretion, either through alternative trafficking of the ASM precursor protein or by means of an unidentified mechanism. Elevation of serum ASM activity has been described in several human diseases, suggesting that patients with diseases involving vascular endothelial cells may exhibit a preferential elevation of serum ASM activity. As acute KD is characterized by systemic vasculitis that could affect vascular endothelial cells, the elevation of serum ASM activity should be considered in these patients. In the present study, serum ASM activity in the sera of 15 patients with acute KD was determined both before and after treatment with infusion of high-dose intravenous immunoglobulin (IVIG), a first-line treatment for acute KD. Serum ASM activity before IVIG was significantly elevated in KD patients when compared to the control group (3.85 ± 1.46 nmol/0.1 ml/6 h vs. 1.15 ± 0.10 nmol/0.1 ml/6 h, p < 0.001), suggesting that ASM activation may be involved in the pathophysiology of this condition. Serum ASM activity before IVIG was significantly correlated with levels of C-reactive protein (p < 0.05). These results suggest the involvement of sphingolipid metabolism in the pathophysiology of KD.

Novel TRAPPC2 mutation in a boy with X-linked spondylo-epiphyseal dysplasia tarda.

X-linked spondylo-epiphyseal dysplasia tarda (SEDT) is an X-linked recessive, late-onset, progressive skeletal disorder characterized by mild-to-moderate short-trunked short stature. X-linked SEDT is caused by mutations in the gene TRAPPC2, which is located on chromosome Xp22. In the present study, we identified a novel splice-site mutation, c.93+1G>A, in TRAPPC2 in a 9-year-old Japanese patient who had X-linked SEDT and no family history of the disease. On reverse transcription-polymerase chain reaction, the mutation resulted in a 4 bp frame-shift insertion between exon 3 and exon 4. The present case highlights the importance of genetic analysis for confirmatory diagnosis of X-linked SEDT, especially in cases without a positive family history.

Identification of activity-based biomarkers for early-stage pancreatic tumors in blood using single-molecule enzyme activity screening.

Single-molecule enzyme activity-based enzyme profiling (SEAP) is a methodology to globally analyze protein functions in living samples at the single-molecule level. It has been previously applied to detect functional alterations in phosphatases and glycosidases. Here, we expand the potential for activity-based biomarker discovery by developing a semi-automated synthesis platform for fluorogenic probes that can detect various peptidases and protease activities at the single-molecule level. The peptidase/protease probes were prepared on the basis of a 7-amino-4-methylcoumarin fluorophore. The introduction of a phosphonic acid to the core scaffold made the probe suitable for use in a microdevice-based assay, while phosphonic acid served as the handle for the affinity separation of the probe using Phos-tag. Using this semi-automated scheme, 48 fluorogenic probes for the single-molecule peptidase/protease activity analysis were prepared. Activity-based screening using blood samples revealed altered single-molecule activity profiles of CD13 and DPP4 in blood samples of patients with early-stage pancreatic tumors. The study shows the power of single-molecule enzyme activity screening to discover biomarkers on the basis of the functional alterations of proteins.

GGT1 is a SNP eQTL gene involved in STAT3 activation and associated with the development of Post-ERCP pancreatitis.

Post-ERCP pancreatitis (PEP) is an acute pancreatitis caused by endoscopic-retrograde-cholangiopancreatography (ERCP). About 10% of patients develop PEP after ERCP. Here we show that gamma-glutamyltransferase 1 (GGT1)-SNP rs5751901 is an eQTL in pancreatic cells associated with PEP and a positive regulator of the IL-6 amplifier. More PEP patients had the GGT1 SNP rs5751901 risk allele (C) than that of non-PEP patients at Hokkaido University Hospital. Additionally, GGT1 expression and IL-6 amplifier activation were increased in PEP pancreas samples with the risk allele. A mechanistic analysis showed that IL-6-mediated STAT3 nuclear translocation and STAT3 phosphorylation were suppressed in GGT1-deficient cells. Furthermore, GGT1 directly associated with gp130, the signal-transducer of IL-6. Importantly, GGT1-deficiency suppressed inflammation development in a STAT3/NF-κB-dependent disease model. Thus, the risk allele of GGT1-SNP rs5751901 is involved in the pathogenesis of PEP via IL-6 amplifier activation. Therefore, the GGT1-STAT3 axis in pancreas may be a prognosis marker and therapeutic target for PEP.

Autophagy-related protein 32 acts as autophagic degron and directly initiates mitophagy.

Autophagy-related degradation selective for mitochondria (mitophagy) is an evolutionarily conserved process that is thought to be critical for mitochondrial quality and quantity control. In budding yeast, autophagy-related protein 32 (Atg32) is inserted into the outer membrane of mitochondria with its N- and C-terminal domains exposed to the cytosol and mitochondrial intermembrane space, respectively, and plays an essential role in mitophagy. Atg32 interacts with Atg8, a ubiquitin-like protein localized to the autophagosome, and Atg11, a scaffold protein required for selective autophagy-related pathways, although the significance of these interactions remains elusive. In addition, whether Atg32 is the sole protein necessary and sufficient for initiation of autophagosome formation has not been addressed. Here we show that the Atg32 IMS domain is dispensable for mitophagy. Notably, when anchored to peroxisomes, the Atg32 cytosol domain promoted autophagy-dependent peroxisome degradation, suggesting that Atg32 contains a module compatible for other organelle autophagy. X-ray crystallography reveals that the Atg32 Atg8 family-interacting motif peptide binds Atg8 in a conserved manner. Mutations in this binding interface impair association of Atg32 with the free form of Atg8 and mitophagy. Moreover, Atg32 variants, which do not stably interact with Atg11, are strongly defective in mitochondrial degradation. Finally, we demonstrate that Atg32 forms a complex with Atg8 and Atg11 prior to and independent of isolation membrane generation and subsequent autophagosome formation. Taken together, our data implicate Atg32 as a bipartite platform recruiting Atg8 and Atg11 to the mitochondrial surface and forming an initiator complex crucial for mitophagy.

Combined linkage analysis and exome sequencing identifies novel genes for familial goiter.

Familial goiter is a genetic disease showing heterogeneous expression. To identify causative genes, we investigated three multigenerational goiter families with an autosomal dominant inheritance pattern. We performed genome-wide linkage analysis on all the families, combined with whole-exome sequencing in two affected individuals from each family. For linkage analysis, we considered loci with logarithm of odds (LOD) scores >1.5 as candidate regions for identification of rare variants. In one of the families, we found two rare heterozygous missense variants, p.V56M in RGS12 and p.G37D in GRPEL1, which segregate with goiter and are both located within the same haplotype on 4p16. This haplotype was not observed in 150 controls. In the other two families, we identified two additional rare missense variants segregating with goiter, p.A551T in CLIC6 on 21q22.12 and p.V412A in WFS1 on 4p16. In controls, the minor allele frequency (MAF) of p.V412A in WFS1 was 0.017 while p.A551T in CLIC6 was not detected. All identified genes (RGS12, GRPEL1, CLIC6 and WFS1) show expression in the human thyroid gland, suggesting that they may play a role in thyroid gland function. Moreover, these four genes are novel with regard to their involvement in familial goiter, supporting genetic heterogeneity of this disease.

Congenital hyperinsulinism in an infant with paternal uniparental disomy on chromosome 11p15: few clinical features suggestive of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome involving tumor predisposition. BWS is caused by various epigenetic or genetic alterations that disrupt the imprinted genes on chromosome 11p15.5 and the clinical findings of BWS are highly variable. Hyperinsulinemic hypoglycemia is reported in about half of all babies with BWS. We identified an infant with diazoxide-unresponsive congenital hyperinsulinism (HI) without any apparent clinical features suggestive of BWS, but diagnosed BWS by molecular testing. The patient developed severe hyperinsulinemic hypoglycemia within a few hours after birth, with macrosomia and mild hydronephrosis. We excluded mutations in the K(ATP) channel genes on chromosome 11p15.1, but found a rare homozygous single nucleotide polymorphism (SNP) of ABCC8. Parental SNP pattern suggested paternal uniparetal disomy in this region. By microsatellite marker analysis on chromosome 11p15, we could diagnose BWS due to the mosaic of paternal uniparental disomy. Our case suggests that some HI of unknown genetic etiology could involve undiagnosed BWS with no apparent clinical features, which might be diagnosed only by molecular testing.

Head pleomorphic sarcoma showing murine double minute 2 amplification without a well-differentiated liposarcoma component in a pediatric patient.

BACKGROUND: Murine double minute 2 (MDM2) is an oncogene that inhibits p53, leading to decreased apoptosis. Sarcomas showing MDM2 amplification are rare among pediatric patients. CASE: A 14-year-old boy presented with pleomorphic sarcoma of the head showing MDM2 amplification without a well-differentiated liposarcoma component. Although chemotherapy was initially performed to reduce the tumor size before surgery, the tumor did not shrink. The patient underwent complete surgical resection. Microscopic examination revealed a positive surgical margin; thus, postoperative proton-beam radiotherapy was performed. 3 years after the therapy, no sign of recurrence was observed. CONCLUSION: Macroscopic surgical resection combined with adjuvant postoperative radiotherapy was effective against MDM2-amplified pleomorphic sarcoma refractory to neoadjuvant chemotherapy in a pediatric patient.

Knowns and unknowns about congenital hypothyroidism: 2022 update.

Several excellent guidelines and expert opinions on congenital hypothyroidism (CH) are currently available. Nonetheless, these guidelines do not address several issues related to CH in detail. In this review, the authors chose the following seven clinical issues that they felt were especially deserving of closer scrutiny in the hope that drawing attention to them through discussion would help pediatric endocrinologists and promote further interest in the treatment of CH. 1. How high should the levothyroxine (L-T4) dose be for initial treatment of severe and permanent CH? 2. What is the optimal method for monitoring treatment of severe CH? 3. At what level does maternal iodine intake during pregnancy affect fetal and neonatal thyroid function? 4. Does serum thyroglobulin differ between patients with a dual oxidase 2 (DUOX2) variants and those with excess iodine? 5. Who qualifies for a genetic diagnosis? 6. What is the best index for distinguishing transient and permanent CH? 7. Is there any cancer risk associated with CH? The authors discussed these topics and jointly edited the manuscript to improve the understanding of CH and related issues.

Characteristics of Preoperative Arteriosclerosis Evaluated by Cardio-Ankle Vascular Index in Patients with Osteoarthritis before Total Knee Arthroplasty.

PURPOSE: Cardiovascular disease (CVD) is a major risk factor for mortality in patients with osteoarthritis, and comorbidities increase postoperative complications after total knee arthroplasty (TKA). Arteriosclerosis plays a main role in hemodynamic dysfunction and CVD; however, arteriosclerosis has not been preoperatively evaluated before TKA using the cardio-ankle vascular index (CAVI). In this study, we evaluated the degree of preoperative arteriosclerosis using the CAVI in patients undergoing TKA, as well as its correlations with several preoperative patient factors. METHODS: Arteriosclerosis was evaluated in 209 consecutive patients (251 knees) with osteoarthritis who underwent TKA at our institution between May 2011 and June 2022. The CAVI was measured in the supine position 1 day before TKA, and the correlations between the CAVI and several clinical factors were analyzed. RESULTS: The CAVI was normal in 62 knees (25%), borderline in 71 knees (28%), and abnormal in 118 knees (47%). Univariate analysis revealed a moderate positive correlation between preoperative CAVI and age (r = 0.451, p < 0.001) and a weak negative correlation between preoperative CAVI and body weight (r = -0.306, p < 0.001) and body mass index (BMI) (r = -0.319, p < 0.001). Multivariate analysis showed that age (ß = 0.349, p < 0.001) and BMI (ß = -0.235, p < 0.001) were significantly correlated with preoperative CAVI. CONCLUSION: Arteriosclerosis should be carefully managed intraoperatively and postoperatively in patients with osteoarthritis undergoing TKA, particularly in older patients and patients with a low BMI.

Arterial Stiffness, Assessed Using the Cardio-Ankle Vascular Index, before and 2 Years after Total Knee Arthroplasty in Patients with Knee Osteoarthritis.

Purpose: Cardiovascular disease (CVD) is a major risk factor for mortality in patients with osteoarthritis, and such comorbidities increase the risk of postoperative complications following total knee arthroplasty (TKA). Arteriosclerosis plays a major role in hemodynamic dysfunction and CVD; however, the postoperative changes in arteriosclerosis following TKA have not been evaluated. Therefore, we assessed the postoperative changes in arteriosclerosis using the cardio-ankle vascular index (CAVI) in patients undergoing TKA, and its relationships with preoperative patient characteristics. Methods: Arteriosclerosis was prospectively evaluated in 119 consecutive patients (140 knees) (15 males (17), 104 females (123); median age 73 years) with knee osteoarthritis who underwent TKA. CAVI was measured before and 2 years after TKA, and the relationships between CAVI and preoperative age, sex, BMI, physical activity status, comorbidities, clinical score, triglyceride concentration, cholesterol concentration, and smoking history were analyzed. Results: CAVI remained stable or improved in 54 joints (39%) and worsened in 86 joints (61%) 2 years post-operation. The median difference between pre- and postoperative CAVI was 0.2 (-0.3, 0.8), and the only preoperative factor associated with this change was preoperative CAVI (r = -0.469, p < 0.001). No other preoperative factor had a significant effect on postoperative arteriosclerosis. Conclusions: The results suggest that patients who undergo TKA subsequently show less severe arteriosclerosis, and the protective effect of TKA on arterial stiffness is greater in those with a higher preoperative CAVI. TKA may be an effective means of reducing the deterioration of arteriosclerosis associated with knee osteoarthritis, at least in the relatively short term.