Ability of NAD and Sirt1 to epigenetically suppress albuminuria.

The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN.

Neck and shoulder pain in thoracic adolescent idiopathic scoliosis 10 years after posterior spinal fusion.

PURPOSE: We aimed to determine the clinical significance of neck and shoulder pain (NSP) 10 years after posterior spinal fusion (PSF) for thoracic adolescent idiopathic scoliosis (AIS) and the relationship between radiographic parameters and NSP. METHODS: Of 72 patients who underwent PSF for thoracic AIS (Lenke 1 or 2) between 2000 and 2013, we included 52 (46 females; Lenke type 1 in 34 patients and type 2 in 18; mean age, 25.6 years) who underwent NSP evaluation using visual analog scale (VAS, 10 cm) 10 years postoperatively (follow-up rate, 72.2%). Correlation analyses were performed using Spearman's rank correlation coefficient (r). RESULTS: The VAS for NSP was 2.6 cm in median and 3.4 cm in mean at 10 years. The VAS had significant negative correlations with several SRS-22 domain scores (rs = - 0.348 for pain, - 0.347 for function, - 0.308 for mental health, and - 0.372 for total) (p < 0.05). In addition, the VAS score was significantly correlated with cervical lordosis (CL) (rs = 0.296), lumbar lordosis (rs = - 0.299), and sacral slope (rs = 0.362) (p < 0.05). Furthermore, at the 10-year follow-up, CL was significantly negatively correlated with T1 slope (rs = - 0.763) and thoracic kyphosis (TK) (- 0.554 for T1-12 and - 0.344 for T5-12) (p < 0.02). CONCLUSION: NSP was associated with deterioration in SRS-22 scores, indicating that NSP is a clinically significant long-term issue in PSF for thoracic AIS. Restoring or maintaining the TK and T1 slopes, which are controllable factors during PSF, may improve cervical lordosis and alleviate NSP at 10-year follow-up.

PCK1 Protects against Mitoribosomal Defects in Diabetic Nephropathy in Mouse Models.

SIGNIFICANCE STATEMENT: Renal gluconeogenesis plays an important role in the pathogenesis of diabetic nephropathy (DN). Proximal tubular phosphoenolpyruvate carboxykinase1 (PEPCK1) is the rate-limiting enzyme in gluconeogenesis. However, the functions of PEPCK1 have not been elucidated. We describe the novel role of PEPCK1 as a mitoribosomal protector using Pck1 transgenic (TG) mice and knockout mice. Pck1 blocks excessive glycolysis by suppressing the upregulation of excess HK2 (the rate-limiting enzyme of glycolysis). Notably, Pck1 overexpression retains mitoribosomal function and suppresses renal fibrosis. The renal and mitoribosomal protective roles of Pck1 may provide important clues for understanding DN pathogenesis and provide novel therapeutic targets. BACKGROUND: Phosphoenolpyruvate carboxykinase (PEPCK) is part of the gluconeogenesis pathway, which maintains fasting glucose levels and affects renal physiology. PEPCK consists of two isoforms-PEPCK1 and PEPCK2-that the Pck1 and Pck2 genes encode. Gluconeogenesis increases in diabetic nephropathy (DN), escalating fasting and postprandial glucose levels. Sodium-glucose cotransporter-2 inhibitors increase hepatic and renal gluconeogenesis. We used genetically modified mice to investigate whether renal gluconeogenesis and Pck1 activity are renoprotective in DN. METHODS: We investigated the expression of Pck1 in the proximal tubule (PTs) of streptozotocin (STZ)-treated diabetic mice. We studied the phenotypic changes in PT-specific transgenic (TG) mice and PT-specific Pck1 conditional knockout (CKO) mice. RESULTS: The expression of Pck1 in PTs was downregulated in STZ-treated diabetic mice when they exhibited albuminuria. TG mice overexpressing Pck1 had improved albuminuria, concomitant with the mitigation of PT cell apoptosis and deposition of peritubular type IV collagen. Moreover, CKO mice exhibited PT cell apoptosis and type IV collagen deposition, findings also observed in STZ-treated mice. Renal fibrotic changes in CKO mice were associated with increasing defects in mitochondrial ribosomes (mitoribosomes). The TG mice were protected against STZ-induced mitoribosomal defects. CONCLUSION: PCK1 preserves mitoribosomal function and may play a novel protective role in DN.

Quantitative assessment of muscle activity of back and lower extremities, whole body sagittal alignment, body sway, and health-related quality of life in adult spinal deformity patients before and after spinopelvic correction surgery: From the standpoint of the "cone of economy".

BACKGROUND AND AIMS: Pain and muscle fatigue in the low back and lower extremity associated with adult spinal deformity (ASD) markedly limit daily activities and affect quality of life. This study aimed to clarify if spinal correction surgery decreases the muscle activity requirements in relation to alignment and balance parameters. METHODS: Integrated electromyogram (I-EMG) studies of the low back and lower extremity in addition to whole body alignment, body sway, and health-related quality of life (HRQOL) were evaluated in 16 patients with ASD before and after surgery. Sixteen healthy volunteers were included as control subjects. Muscle activities of the bilateral lumbar paravertebral, biceps femoris, rectus femoris, gastrocnemius, and tibialis anterior were measured using surface electromyogram in both resting and working standing positions. Surgical outcomes were based on improvements in muscle fatigue using the sum of the whole muscle I-EMGs and body sway. HRQOL was evaluated by SRS-22r, which measures 4 domains (function, pain, self-image, mental health) and subtotal scores. RESULTS: In controls, the sum of the 10 whole I-EMGs (mVms; mean ± SD) was 3316 ± 1247 in the resting standing position and 5625 ± 2065 in the working standing position. The I-EMG values were higher in ASD patients than in healthy subjects; in the resting standing position, the sum of the whole 10 I-EMGs significantly decreased from baseline (9125 ± 3529) to 3 (6088 ± 1793) and 6 (6381 ± 1776) months postoperatively (p < 0.01). In the working standing position, the sum in ASD patients also significantly decreased from baseline (14,160 ± 5474) to 3 (8085 ± 2540) and 6 (8557 ± 3025) months postoperatively (p < 0.01). I-EMG values did not differ significantly between the 3- and 6-month time points in either condition. Body sway was also improved postoperatively at 3 months and maintained at 6 months along with the amelioration of whole-body sagittal alignment, and 4 domains and subtotal SRS-22r scores significantly increased postoperatively. CONCLUSION: Following spinopelvic correction surgery, whole body sagittal alignment was improved, and muscle activity based on I-EMG and body sway were significantly decreased. The SRS-22r scores after surgery also indicated significant improvement, suggesting that muscle fatigue in the standing position was ameliorated, i.e., the "cone of economy" was normalized.

Nmnat1 Deficiency Causes Mitoribosome Excess in Diabetic Nephropathy Mediated by Transcriptional Repressor HIC1.

Nicotinamide adenine dinucleotide (NAD) is involved in renal physiology and is synthesized by nicotinamide mononucleotide adenylyltransferase (NMNAT). NMNAT exists as three isoforms, namely, NMNAT1, NMNAT2, and NMNAT3, encoded by Nmnat1, Nmnat2, and Nmnat3, respectively. In diabetic nephropathy (DN), NAD levels decrease, aggravating renal fibrosis. Conversely, sodium-glucose cotransporter-2 inhibitors increase NAD levels, mitigating renal fibrosis. In this regard, renal NAD synthesis has recently gained attention. However, the renal role of Nmnat in DN remains uncertain. Therefore, we investigated the role of Nmnat by establishing genetically engineered mice. Among the three isoforms, NMNAT1 levels were markedly reduced in the proximal tubules (PTs) of db/db mice. We examined the phenotypic changes in PT-specific Nmnat1 conditional knockout (CKO) mice. In CKO mice, Nmnat1 expression in PTs was downregulated when the tubules exhibited albuminuria, peritubular type IV collagen deposition, and mitochondrial ribosome (mitoribosome) excess. In CKO mice, Nmnat1 deficiency-induced mitoribosome excess hindered mitoribosomal translation of mitochondrial inner membrane-associated oxidative phosphorylation complex I (CI), CIII, CIV, and CV proteins and mitoribosomal dysfunction. Furthermore, the expression of hypermethylated in cancer 1, a transcription repressor, was downregulated in CKO mice, causing mitoribosome excess. Nmnat1 overexpression preserved mitoribosomal function, suggesting its protective role in DN.

Racial differences in whole-body sagittal alignment between Asians and Caucasians based on international multicenter data.

PURPOSE: To examine inherent differences adjusted for age and clinical score in whole-body sagittal (WBS) alignment involving the lower extremities between Asians and Caucasians, and to determine the relationship between age and WBS parameters by race and sex. METHODS: A total of 317 individuals consisting of 206 Asians and 111 Caucasians participated. WBS parameters including C2-7 lordotic angle, lower lumbar lordosis (lower LL, L4-S), pelvic incidence (PI), pelvic thickness, knee flexion (KF), sagittal vertical axis (SVA), and T1 pelvic angle (TPA) were evaluated radiologically. Propensity score-matching adjustments for age and the Oswestry Disability Index scores for comparative analysis between the two race cohorts and correlation analysis between age and WBS parameters for all subjects by race and sex were conducted. RESULTS: The comparative analysis included 136 subjects (age: Asians 41.1 ± 13.5, Caucasians 42.3 ± 16.2 years, p = 0.936). Racial differences in WBS parameters were observed in C2-7 lordotic angle (-1.8 ± 12.3 vs. 6.3 ± 12.2 degrees, p = 0.001), and lower LL (34.0 ± 6.6 vs. 38.0 ± 6.1 degrees, p < .001). In correlation analysis with age, moderate or more significant correlations with age were found in KF for all groups, and in SVA and TPA for females of both racial groups. Age-related changes in pelvic parameters of PI and pelvic thickness were more significant in Caucasian females. CONCLUSION: Analysis of the correlation between age and WBS parameters suggested that age-related WBS changes vary between races and should be considered during corrective spinal surgery.

The age-specific normative values of standing whole-body sagittal alignment parameters in healthy adults: based on international multicenter data.

PURPOSE: To investigate the age-specific normative values of whole-body sagittal alignment (WBSA) including global balance parameters in healthy adults and to clarify the correlations among parameters based on the data from three international multicenter. METHODS: Three hundred and seventeen healthy subjects (range: 20-84 y.o., mean: 43.8 ± 14.7 y.o.) were included and underwent whole-body biplanar X-ray imaging system. Spinopelvic parameters and knee flexion (KF), the center of acoustic meatus (CAM)-hip axis (HA), and C2 dentiform apophyse (OD)-HA, the cranial center (Cr)-HA were evaluated radiologically. Sub-analysis for correlation analysis between age and parameters and among parameters was performed to investigate age-specific change and compensatory mechanisms. RESULTS: For age-related change, C2-7 angle (r = .326 for male/.355 for female), KF (r = .427/.429), and SVA (r = .234/.507) increased with age in both male and female group. For global parameters related to the center of the gravity, correlations with age were not significant (r = .120/.161 for OD-HA, r = .163/.275 for Cr-HA, r = .149/.262 for CAM-HA). Knee flexion (KF) has correlation with global parameters (i.e., SVA, OD-HA, Cr-HA, CAM-HA) and does not have correlations with local spinopelvic alignment. CONCLUSION: While several local alignment changes with age were found, changes in global parameters related to the center of gravity were kept relatively mild by the chain of compensation mechanisms including the lower limbs. We showed the normative values for a comprehensive WBSA in standing posture from large international healthy subjects' database.

Evaluating flexibility and predicting curve correction using fulcrum-bending radiographs in Lenke type 2 adolescent idiopathic scoliosis.

BACKGROUND: Fulcrum-bending (FB) correction is considered to provide the best estimation of main thoracic (MT) curve flexibility and postoperative correction in surgical treatment for adolescent idiopathic scoliosis (AIS). However, few studies evaluated the usefulness of FB radiographs for proximal thoracic (PT) curve. We aimed to perform flexibility assessments using both active side-bending (SB) and FB radiographs and evaluate surgical outcomes after posterior spinal fusion (PSF) for Lenke type 2 AIS. METHODS: This study included 38 consecutive patients with Lenke type 2 AIS who underwent PSF using a pedicle screw construct with a minimum 2-year follow-up. Radiographic parameters, including correction rate, SB and FB flexibility, and FB correction index (FBCI: [correction rate/FB flexibility] × 100), were evaluated preoperatively, immediately after surgery, and at the 2-year follow-up. The clinical outcomes were preoperatively evaluated using the Scoliosis Research Outcomes Instrument-22 and at the follow-up. RESULTS: All scoliosis curves significantly improved and shoulder balance shifted toward left shoulder elevation (all comparisons, p < 0.0001). There were significant differences between the SB and FB corrections in the PT and MT curves (p < 0.0001). The magnitudes of the discrepancies between the SB and FB corrections in the PT and MT curves were 11.2° ± 5.2° and 11.6° ± 7.2°, respectively. FB correction did not differ from postoperative Cobb angles correction immediately after surgery or at the 2-year follow-up; the mean FBCIs in the PT and MT curves were 98.8% and 105.5%, respectively. The self-image domain SRS-22 scores had significantly increased at the 2-year follow-up (p < 0.0001). CONCLUSIONS: There were significant differences between the SB and FB corrections, and FB correction tended to approximate the postoperative curve correction (FBCI = 100%) for PT and MT curves in patients with Lenke type 2 AIS. FB flexibility is more reliable than SB flexibility in evaluating actual curve flexibility even for the PT curve.

Usefulness and limitations of intraoperative pathological diagnosis using frozen sections for spinal cord tumors.

BACKGROUND: Intraoperative pathological diagnosis has a major influence on the intra- and postoperative management of spinal cord tumors. Thus, the aim of this study was to assess the reliability of intraoperative pathological diagnosis for spinal cord lesions by comparing it with the final pathological diagnosis and to determine its usefulness and limitations. METHOD: Three-hundred and three consecutive patients (mean age, 53.9 years) with neoplastic spinal cord lesions who underwent initial surgery between 2000 and 2021 were included. The anatomical locations of the spinal cord tumors and the implementation rate of intraoperative pathological diagnosis in each tumor type were evaluated. As the primary outcome, we determined the concordance rates between the intraoperative pathological diagnosis and the final diagnosis. When the intraoperative pathological diagnosis and final diagnosis were the same, the diagnosis was defined as a "match." Otherwise, the diagnosis was defined as a "mismatch." RESULTS: The overall implementation rate of intraoperative pathological diagnosis was 53%, with implementation rates of 71%, 45%, 47%, and 50% for intramedullary, intradural extramedullary, extradural, and dumbbell tumors, respectively. The overall concordance rate was 87.6%, with concordance rates of 80%, 95%, 75%, and 90% for intramedullary, intradural extramedullary, extradural, and dumbbell tumors, respectively (p < 0.05). The diagnoses of ependymomas, low-grade astrocytomas, and high-grade astrocytomas was occasionally difficult among intramedullary tumors. Among intradural extramedullary tumors, differentiation between grade 1 meningioma and high-grade meningioma was difficult using intraoperative pathological diagnosis. CONCLUSIONS: Surgeons must recognize the lower accuracy of intraoperative pathological diagnosis for intramedullary and extradural lesions and make a final decision by considering the intraoperative gross findings, preoperative clinical course, and imaging.

Characteristics of back pain in patients with adolescent idiopathic scoliosis: Considerations in candidates for corrective surgery.

BACKGROUND: Previous studies have demonstrated that the point prevalence of back pain ranges from 12 % to 33 % and that the lifetime prevalence of back pain ranges from 28 % to 51 % in adolescents. However, few studies on back pain in patients with Adolescent idiopathic scoliosis (AIS) have been conducted, and these studies had significant limitations, including a lack of comparative controls and detailed information about scoliotic deformity or pain location. This study aimed to determine whether adolescents with AIS experience back pain in specific regions. METHODS: This retrospective case-control study included 189 female adolescents with AIS who underwent corrective fusion from 2008 to 2020. Questionnaires on back pain and health-related quality of life (HRQOL) using the Scoliosis Research Society Outcomes Instrument-22 (SRS-22) were conducted preoperatively. The control group included 2909 general female adolescents. RESULTS: The mean Cobb angles in the main thoracic and thoracolumbar/lumbar curves were 51.4 ± 15.3° and 40.4 ± 12.9°. Back pain characteristics included higher point prevalence (25.9 %) and lifetime prevalence (64.6 %) compared to healthy controls. Adolescents with back pain showed lower scores in the pain and mental health domains of the SRS-22. Adolescents with major thoracic AIS showed more back pain in the upper and middle right back compared to adolescents with major thoracolumbar/lumbar AIS. CONCLUSION: The point and lifetime prevalence of back pain were definitely higher in patients with AIS, which affected their HRQOL. There was a relationship between pain around the right scapula and the right major thoracic curve with a rib hump deformity.

Scoliosis Research Society-22r score is affected by standing whole body sagittal alignment, age, and sex, but not by standing balance or skeletal muscle mass in healthy volunteers.

PURPOSE: Aging and spinal disease impair standing whole body sagittal alignment (WBS alignment), which leads to stooping. When WBS alignment deteriorates, compensatory mechanisms are activated to maintain standing posture. Increase of the compensation impairs health-related quality of life (HRQOL). The purpose of this research was to determine whether postural factors, age, and sex affect HRQOL. METHODS: This cross-sectional study evaluated the influence of WBS alignment, standing body sway (balance), skeletal muscle mass (SMM), aging, and sex on HRQOL in healthy volunteers (n = 150; mean age 40.9 years [20-76], 96 women). Age, sex, weight, height, and body mass index (BMI) were obtained. HRQOL was assessed with Scoliosis Research Society-22 (SRS-22r). WBS alignment and balance were measured by EOS imaging with simultaneous force plate measurement. SMM was measured using a medical body composition analyzer. Based on the bivariate analysis between the SRS-22r subtotal and all parameters, selected ten parameters were used for multivariate logistic regression analysis to identify affecting factors to SRS-22r. RESULTS: Men had significantly higher weight, height, BMI, and SRS-22r score in all domains. The L4-S1 lumbar lordosis angle was greater in men, and pelvic tilt and knee hyperextension were greater in women. Women had a more stable standing posture, whereas men had significantly higher SMM values. Multivariate logistic regression analysis revealed that age, sex, and TPA were identified as significant factors affecting SRS-22r. CONCLUSIONS: In healthy volunteers, SRS-22r is affected by aging, sex (woman had a lower score), and sagittal malalignment. Neither Standing balance nor SMM, however, affect SRS-22r.4.

Pelvic thickness, sex, ethnicity, and age affect pelvic incidence in healthy volunteers of Multi-Ethnic Alignment Normative Study (MEANS) database.

BACKGROUND: The purpose of this study was to investigate the affecting factors on pelvic incidence (PI) and to test the hypothesis that PI changes even after skeletal maturity probably due to hypermobility of the sacroiliac joint using a large international multi-center database. METHODS: A prospective and cross-sectional healthy adult volunteers, ages 18-80 years, across 5 countries were used. Radiographic measurements included standard whole body alignment parameters. Bivariate regression analyses between PI versus demographics and spino-pelvic anatomical parameters were performed. An effect of sex on pelvic anatomical parameters was also investigated. Multivariate logistic regression with a forward stepwise procedure was performed to identify the contributing factors to PI, and an appropriate model was obtained. RESULTS: PI showed a significant positive correlation with age in pooled data. Divided by sex, however, there was no correlation in men, but women showed a significant higher correlation coefficient. Pelvic thickness (PTh) had a significant negative correlation with age in pooled data. Divided by sex, no correlation was found in men, but there was a significant correlation in women with higher correlation coefficient. The stepwise multivariate analysis for the factors on PI identified four significant factors: age, sex, ethnicity, and PTh. CONCLUSIONS: PTh, sex, ethnicity, and age affected PI. There was a positive correlation between PI and age. The tendency was more significant in woman than in man. The results support the hypothesis that PI increases with aging, but the change seems to be small and needs to be verified in a longitudinal evaluation.

Correlation analysis of the PI-LL mismatch according to the pelvic incidence from a database of 468 asymptomatic volunteers.

PURPOSE: Previous studies on adults with degenerative scoliosis (ADS) have been fixed the threshold of PI-LL mismatch less than 10° for achieving good clinical outcomes. Recent studies discussed that PI-LL mismatch should consider individual pelvic incidence (PI) and should be set first in a normal population. The purpose of this study is to assess the variability of PI-LL mismatch according to PI in an asymptomatic population. METHODS: Full-body low dose stereoradiographic evaluation was done in a multi-ethnic cohort of 468 asymptomatic adult volunteers. Patients were clustered in three groups depending on individual PI values: PI < 45°, 45° < PI < 60° and PI > 60°. 3D measurements were performed using a commercially available 2D/3D modeling software to establish a correlation of PI with other spinopelvic parameters. ANOVA and Tukey's HSD for post-hoc analysis were used to determine the differences between the three groups. RESULTS: In our asymptomatic population, the mean value of PI-LL mismatch is - 5.4° ± 10.7°. Clusterization of the population reveals significant differences in the distribution of L1S1 lordosis, pelvic tilt and PI-LL with positive linear correlation according to PI values. As an interestingly result, PI-LL mismatch is equal to 0° when PI is around 64°. CONCLUSIONS: The present study demonstrated that PI-LL mismatch is negative in an asymptomatic population (- 5.4° ± 10.7°) and the value should be customized to each patient to be able to restore the appropriate lordosis in ADS. The PI-LL mismatch is given by the formula PI-LL = - 28.5 + 0.44 × PI.

Gravity center estimation for evaluation of standing whole body compensation using virtual barycentremetry based on biplanar slot-scanning stereoradiography - validation by simultaneous force plate measurement.

BACKGROUND: Whole body standing alignment (WBSA) in terms of biomechanics can be evaluated accurately only by referring the gravity line (GL) which lies on the gravity center (GC). Here, we introduce a method for estimating GL and simultaneous WBSA measurement using the EOS® imaging system and report on the reproducibility and reliability of the method. METHODS: A 3-dimensional (3D) avatar to estimate GC was created following three steps: 3D reconstruction of the bone based on EOS images; deformation into a generic morphotype (MakeHuman statistical model) before density integration with 3D rasterization of the full body into 1-mm3 voxels (the content of each voxel is considered homogeneous); computation of the density of all the voxels provides the center of mass, which can be projected onto the floor as the GC of the full body, providing the GL in relation to the WBSA. The repeatability, reproducibility, and accuracy of the estimated GC and body weight of the avatar were compared with clinical estimation using a force plate in healthy volunteers and patients with degenerative and deformative diseases. RESULTS: Statistical analyses of the data revealed that the repeatability and reproducibility of the estimation was high with intra-rater and inter-rater intraclass correlation coefficient. ≥0.999. The coordinate values of the GC and body weight estimation did not differ significantly between the avatar and force plate measurements, demonstrating the high accuracy of the method. CONCLUSION: This new method of estimating GC and WBSA is reliable and accurate. Application of this method could allow clinicians to quickly and qualitatively evaluate WBSA with GL with various spinal malalignment pathologies.

Pre-emptive Short-term Nicotinamide Mononucleotide Treatment in a Mouse Model of Diabetic Nephropathy.

BACKGROUND: The activation of NAD+-dependent deacetylase, Sirt1, by the administration of nicotinamide mononucleotide (NMN) ameliorates various aging-related diseases. METHODS: Diabetic db/db mice were treated with NMN transiently for 2 weeks and observed for effects on diabetic nephropathy (DN). RESULTS: At 14 weeks after the treatment period, NMN attenuated the increases in urinary albumin excretion in db/db mice without ameliorating hemoglobin A1c levels. Short-term NMN treatment mitigated mesangium expansion and foot process effacement, while ameliorating decreased Sirt1 expression and increased claudin-1 expression in the kidneys of db/db mice. This treatment also improved the decrease in the expression of H3K9me2 and DNMT1. Short-term NMN treatment also increased kidney concentrations of NAD+ and the expression of Sirt1 and nicotinamide phosphoribosyltransferase (Nampt), and it maintained nicotinamide mononucleotide adenyltransferase1 (Nmnat1) expression in the kidneys. In addition, survival rates improved after NMN treatment. CONCLUSIONS: Short-term NMN treatment in early-stage DN has remote renal protective effects through the upregulation of Sirt1 and activation of the NAD+ salvage pathway, both of which indicate NMN legacy effects on DN.

Influence of lumbosacral transitional vertebrae on spinopelvic parameters using biplanar slot scanning full body stereoradiography-analysis of 291 healthy volunteers.

BACKGROUND: Proper identification of lumbosacral transitional vertebrae (LSTV) is important to characterize the relationship between the transitional segment and adjacent levels. Classical classification schemes are inaccurate with respect to the whole spine. We propose a precise vertebral numbering method and investigated the relationship between LSTV and whole-body sagittal alignment. METHODS: A total of 291 healthy adult volunteers with no history of spinal disease were evaluated with biplanar slot scanning full body stereoradiography to determine the prevalence of LSTV. Vertebrae were counted from the first cervical vertebra using both coronal and sagittal plane images. We then investigated the influence of LSTV on whole-body sagittal alignment in 279 participants. Whole-body key parameters descriptive statistics were compared among groups according to the number of vertebrae (L4, L5, and L6). Statistical analysis was performed between normal and LSTV cases using the Steel-Dwass analysis. RESULTS: Of the 291 subjects, 14 (4.8%) had 23 vertebrae and 16 (5.5%) had 25 vertebrae. Eleven (3.8%) had Th11, 3 (1.0%) had L4, and 1 (0.3%) had Th11 + L6, 16 (5.5%) had L6. Compared with the normal group, the sacral base in relation to the pelvis was higher in the L4 group and lower in the L6 group. The C2-C7 angle and lumbar lordosis (LL) were increased in both the L4 and L6 groups. All remaining parameters were decreased in the L4 group and increased in the L6 group. The relationship between LL and PI was similar in the normal and LSTV groups, despite the difference in the sacral base location. CONCLUSIONS: We propose a precise method for numbering the vertebrae using coronal and sagittal full body images. The spinopelvic parameters of the LSTV population significantly differed from those in the normal spine population due to differences in the sacral base location.

Does intraoperative periprosthetic occult fracture of the acetabulum affect clinical outcomes after primary total hip arthroplasty?

INTRODUCTION: The frequency of intraoperative periprosthetic occult fracture of the acetabulum (IPOA) in primary total hip arthroplasty (THA) is relatively high. However, the effect of this fracture on clinical outcome and survival of primary THA remains unknown. This study aimed to determine the impact of IPOA on the outcomes of primary THA during a minimum follow-up of 5 years. MATERIALS AND METHODS: This retrospective case-control study compared the outcomes of primary THA with or without IPOA during a minimum 5-year follow-up. Thirty-eight patients who underwent primary THA with IPOA (O group) were matched to 76 patients without IPOA (C group) between 2004 and 2013 based on age, sex, body mass index, primary diseases, cup diameter, cup design, and additional dome screw. Both groups underwent the same rehabilitation programs after surgery. We evaluated the Japanese Orthopaedic Association clinical outcomes score; postoperative complications, such as nerve injury, dislocation, heterotopic ossification, iliopsoas impingement, or infection; and radiographic outcomes. Additionally, we performed Kaplan-Meier survival analysis with cup aseptic loosening, cup failure revision, and all-cause revision as the endpoints. RESULTS: There were no significant differences in the pre- and postoperative clinical scores, postoperative complication rates, and cup sagittal rotation between the two groups. Radiographic evaluations showed no aggravation of cases to overt fractures. Bone ingrowth was observed in all cases, and none of the acetabular cups had a progressive radiolucent line ≥ 2 mm in all the 3 acetabular zones. Ten-year survival rates for cup aseptic loosening and cup failure revision were 100% in both groups; those for all-cause revision were 97.4% (92.0-100%) and 100% in the O and C groups, respectively (p = 0.157). CONCLUSIONS: Primary THA with IPOA provides favorable mid- to long-term outcomes. On IPOA diagnosis, although radiographic follow-up is necessary, additional treatments or rehabilitation programs are not required. Furthermore, postoperative computed tomography images for the detection of IPOA may be unnecessary.

The odontoid-CSVL distance in a global population of asymptomatic volunteers: normative values and implications for spinal coronal alignment.

PURPOSE: In a population of asymptomatic volunteers across 5 countries, we sought to: (a) establish normative values of the Odontoid-Central Sacral Vertical Line (OD-CSVL) across patient factors, and (b) assess correlations of OD-CSVL with other radiographic parameters. METHODS: A prospective, cross-sectional study of asymptomatic adult volunteers, ages 18-80 years, were enrolled across 5 countries (France, Japan, Singapore, Tunisia, United States) forming the Multi-Ethnic Alignment Normative Study (MEANS) cohort. Included volunteers had no known spinal disorder(s), no significant neck/back pain (VAS ≤ 2; ODI ≤ 20), and no significant scoliosis (Cobb ≤ 20°). Radiographic measurements included commonly used coronal alignment parameters (mm) and angles (°). OD-CSVL was defined as the difference between the odontoid plumb line (line from the tip of the odontoid vertically down) and the CSVL (vertical line from the center of the sacrum). Chi-square, student's t tests, Kruskal-Wallis, Wilcoxon rank-sum, linear regression, and Pearson's correlation were used with significance at p < 0.05. RESULTS: 467 volunteers were included with normative OD-CSVL values by age decade, gender, BMI, and country. Mean ± SD OD-CSVL was 8.3 mm ± 6.5 mm and 31 (6.6%) volunteers were almost perfectly aligned (OD-CSVL < 1 mm). A linear relationship was seen between OD-CSVL with both age (p < 0.001) and BMI (p = 0.015). Significant variation was seen between OD-CSVL and 5 different ethnicities (p = 0.004). OD-CSVL correlated best with other coronal radiographic parameters, C7-CSVL (r = 0.743, p < 0.001), OD-knee (r = 0.230, p < 0.001), CAM-knee (r = 0.612, p < 0.001), and regional TL cobb angle (r = 0.4214, p = 0.005). CONCLUSION: Among asymptomatic volunteers, increased OD-CSVL was significantly associated with increased age, increased BMI, and ethnicity, but not gender. OD-CSVL correlated strongest with C7-CSVL, TL cobb angle, OD-knee, and CAM-knee. OD-CSVL. These results support further study of OD-CSVL in symptomatic adult spine deformity patients.

The influence of pelvic tilt on stress distribution in the acetabulum: finite element analysis.

BACKGROUND: Finite element analysis (FEA) has been previously applied for the biomechanical analysis of acetabular dysplasia and osteotomy. However, until now, there have been little reports on the use of FEA to evaluate the effects of pelvic tilt on stress distribution in the acetabulum. METHODS: We used the Mechanical Finder Ver. 7.0 (RCCM, Inc., Japan) to construct finite element models based on 3D-CT data of patients, and designed dysplasia, borderline, and normal pelvic models. For analysis, body weight was placed on the sacrum and the load of the flexor muscles of the hip joint was placed on the ilium. The pelvic tilt was based on the anterior pelvic plane, and the pelvic tilt angles were -20°, 0°, and 20°. The load of the flexor muscle of the hip joint was calculated using the moment arm equation. RESULTS: All three models showed the highest values of von Mises stress in the -20° pelvic tilt angle, and the lowest in the 20° angle. Stress distribution concentrated in the load-bearing area. The maximum values of von Mises stress in the borderline at pelvic tilt angles of -20° was 3.5Mpa, and in the dysplasia at pelvic tilt angles of 0° was 3.1Mpa. CONCLUSIONS: The pelvic tilt angle of -20° of the borderline model showed equal maximum values of von Mises stress than the dysplasia model of pelvic tilt angle of 0°, indicating that pelvic retroversion of -20° in borderline is a risk factor for osteoarthritis of the hip joints, similar to dysplasia.

Sacral incidence to pubis: a novel and alternative morphologic radiological parameter to pelvic incidence in assessing spinopelvic sagittal alignment.

BACKGROUND: Although pelvic incidence (PI) is a key morphologic parameter in assessing spinopelvic sagittal alignment, accurate measurements of PI become difficult in patients with severe hip dislocation or femoral head deformities. This study aimed to investigate the reliability of our novel morphologic parameters and the correlations with established sagittal spinopelvic parameters. METHODS: One hundred healthy volunteers (25 male and 75 female), with an average age of 38.9 years, were analysed. Whole-body alignment in the standing position was measured using a slot-scanning X-ray imager. We measured the established spinopelvic sagittal parameters and a novel parameter: the sacral incidence to pubis (SIP). The correlation coefficient of each parameter, regression equation of PI using SIP, and regression equation of lumbar lordosis (LL) using PI or SIP were obtained. The intraclass correlation coefficient (ICC) was calculated as an evaluation of the measurement reliability. RESULTS: Reliability analysis showed high intra- and inter-rater agreements in all the spinopelvic parameters, with ICCs > 0.9. The SIP and pelvic inclination angle (PIA) demonstrated strong correlation with PI (R = 0.96) and pelvic tilt (PT) (R = 0.92). PI could be predicted according to the regression equation: PI = - 9.92 + 0.905 * SIP (R = 0.9596, p < 0.0001). The ideal LL could be predicted using the following equation using PI and age: ideal LL = 32.33 + 0.623 * PI - 0.280 * age (R = 0.6033, p < 0.001) and using SIP and age: ideal LL = 24.29 + 0.609 * SIP - 0.309 * age (R = 0.6177, p < 0.001). CONCLUSIONS: Both SIP and PIA were reliable parameters for determining the morphology and orientation of the pelvis, respectively. Ideal LL was accurately predicted using the SIP with equal accuracy as the PI. Our findings will assist clinicians in the assessment of spinopelvic sagittal alignment. TRIAL REGISTRATION: This study was retrospectively registered with the UMIN Clinical Trials Registry ( UMIN000042979 ; January 13, 2021).