Painful Diabetic Neuropathy Is Associated With Greater Autonomic Dysfunction Than Painless Diabetic Neuropathy

Objective: Although a clear link between diabetic peripheral neuropathy (DPN) and autonomic neuropathy is recognized, the relationship of autonomic neuropathy with subtypes of DPN is less clear. This study aimed to investigate the relationship of autonomic neuropathy with painless and painful DPN. Research design and methods: Eighty subjects (20 healthy volunteers, 20 with no DPN, 20 with painful DPN, 20 with painless DPN) underwent detailed neurophysiological investigations (including conventional autonomic function tests [AFTs]) and spectral analysis of short-term heart rate variability (HRV), which assesses sympathovagal modulation of the heart rate. Various frequency-domain (including low frequency [LF], high frequency [HF], and total power [TP]) and time-domain (standard deviation of all normal-to-normal R-R intervals [SDNN] and root mean square of successive differences [RMSSD]) parameters were assessed. Results: HRV analysis revealed significant differences across the groups in LF, HF, TP, SDNN, and RMSSD (ANOVA P < 0.001). Subgroup analysis showed that compared with painless DPN, painful DPN had significantly lower HF (3.59 ± 1.08 [means ± SD] vs. 2.67 ± 1.56), TP (5.73 ± 1.28 vs. 4.79 ± 1.51), and SDNN (2.91 ± 0.65 vs. 1.62 ± 3.5), P < 0.05. No significant differences were seen between painless DPN and painful DPN using an AFT. Conclusions: This study shows that painful DPN is associated with significantly greater autonomic dysfunction than painless DPN. These changes are only detected using spectral analysis of HRV (a simple test based on a 5-min electrocardiogram recording), suggesting that it is a more sensitive tool to detect autonomic dysfunction, which is still under-detected in people with diabetes. The greater autonomic dysfunction seen in painful DPN may reflect more predominant small fiber involvement and adds to the growing evidence of its role in the pathophysiology of painful DPN

Personalised 3D knee compliance from clinically viable knee laxity measurements: A proof of concept ex vivo experiment.

Personalised information of knee mechanics is increasingly used for guiding knee reconstruction surgery. We explored use of uniaxial knee laxity tests mimicking Lachman and Pivot-shift tests for quantifying 3D knee compliance in healthy and injured knees. Two healthy knee specimens (males, 60 and 88 years of age) were tested. Six-degree-of-freedom tibiofemoral displacements were applied to each specimen at 5 intermediate angles between 0° and 90° knee flexion. The force response was recorded. Six-degree-of-freedom and uniaxial tests were repeated after sequential resection of the anterior cruciate, posterior cruciate and lateral collateral ligament. 3D knee compliance (C6DOF) was calculated using the six-degrees-of-freedom measurements for both the healthy and ligament-deficient knees and validated using a leave-one-out cross-validation. 3D knee compliance (CCT) was also calculated using uniaxial measurements for Lachman and Pivot-shift tests both conjointly and separately. C6DOF and CCT matrices were compared component-by-component and using principal axes decomposition. Bland-Altman plots, median and 40-60th percentile range were used as measurements of bias and dispersion. The error on tibiofemoral displacements predicted using C6DOF was < 9.6% for every loading direction and after release of each ligament. Overall, there was good agreement between C6DOF and CCT components for both the component-by-component and principal component comparison. The dispersion of principal components (compliance coefficients, positions and pitches) based on both uniaxial tests was lower than that based on single uniaxial tests. Uniaxial tests may provide personalised information of 3D knee compliance

Evidence for gender-specific bone loss mechanisms in periprosthetic osteolysis

Osteolysis adjacent to total hip replacement (THR) prostheses is a major cause of their eventual failure. Periprosthetic osteolysis is associated with the production of bioactive particles, produced by the wear of articulating prosthesis surfaces. Wear particles invade the periprosthetic tissue, inducing inflammation and bone resorption. Previous studies have shown that osteocytes, the most numerous cell type in mineralised bone, can respond to wear particles of multiple orthopaedic material types. Osteocytes play important roles in bone resorption, regulating bone resorption by osteoclasts and directly through osteocytic osteolysis, also known as perilacunar remodelling. In this study, we perform a histological analysis of bone biopsies obtained from cohorts of male and female patients undergoing either primary THR surgery or revision THR surgery for aseptic loosening. The osteocyte lacunae area (Ot.Lac.Ar) and percentage lacunar area/bone area (%Ot.Lac.Ar/B.Ar) were significantly larger overall in revision THR bone than bone from similar sites in primary THR. Analysis by patient gender showed that increased Ot.Lac.Ar, indicative of increased perilacunar remodelling, was restricted to female revision samples. No significant differences in osteoclast parameters were detectable between the cohorts. These findings suggest previously unrecognised gender-specific mechanisms of bone loss in orthopaedic wear particle-induced osteolysis in humans.Renee T. Ormsby, Lucian B. Solomon, Roumen Stamenkov, David M. Findlay and Gerald J. Atkin

The effect of surgical change to hip geometry on hip biomechanics after primary total hip arthroplasty

First published: 06 October 2022. OnlinePublThe aim of this study was to determine the effect of surgical change to the acetabular offset and femoral offset on the abductor muscle and hip contact forces after primary THA using computational methods. Thirty-five patients undergoing primary THA were recruited. Patients underwent a computed tomography scan of their pelvis and hip, and underwent gait analysis pre- and 6-months post-operatively. Surgically induced changes in acetabular and femoral offset were used to inform a musculoskeletal model to estimated abductor muscle and hip joint contact forces. Two experiments were performed: (1) influence of changes in hip geometry on hip biomechanics with preoperative kinematics; and (2) influence of changes in hip geometry on hip biomechanics with postoperative kinematics. Superior and medial placement of the hip centre of rotation during THA was most influential in reducing hip contact forces, predicting 63% of the variance (p<0.001). When comparing the preoperative geometry and kinematics model, with postoperative geometry and kinematics, hip contact forces increased after surgery (0.68 BW, p=0.001). Increasing the abductor lever arm reduced abductor muscle force by 28% (p<0.001) and resultant hip contact force by 17% (0.6 BW, p=0.003), with both preoperative and postoperative kinematics. Failure to increase abductor lever arm increased resultant hip contact force 11% (0.33 BW, p<0.001). In conclusion, increasing the abductor lever arm provides a substantial biomechanical benefit to reduce hip abductor and resultant hip joint contact forces. The magnitude of this effect is equivalent to the average increase in hip contact force seen with improved gait from pre-to post-surgery. This article is protected by copyright. All rights reserved.Jasvir S. Bahl, John B. Arnold, David J. Saxby, Mark Taylor, Lucian B. Solomon, Dominic Thewli

Change in CT-measured acetabular bone density following total hip arthroplasty: a systematic review and meta-analysis

Background and purpose - Assessing peri-acetabular bone quality is valuable for optimizing the outcomes of pri- mary total hip arthroplasty (THA) as preservation of good quality bone stock likely affects implant stability. The aim of this study was to perform a meta-analysis of peri-acetabular bone mineral density (BMD) changes over time measured using quantitative computer tomography (CT) and, second, to investigate the influence of age, sex, and fixation on the change in BMD over time.Methods - A systematic search of Embase, Scopus, Web of Science, and PubMed databases identified 19 studies that measured BMD using CT following THA. The regions of interest (ROI), reporting of BMD results, and scan protocols were extracted. A meta-analysis of BMD was performed on 12 studies that reported measurements immediately postop- eratively and at follow-up.Results - The meta-analysis determined that peri- acetabular BMD around both cemented and uncemented components decreases over time. The amount of BMD loss increased relative to proximity of the acetabular component. There was a greater decrease in cortical BMD over time in females and cancellous BMD for young patients of any sex.Conclusion - Peri-acetabular BMD decreases at differ- ent rates relative to its proximity to the acetabular component. Cancellous BMD decreases more in young patients and cor- tical bone decreases more in females. Standardized reporting parameters and suggested ROI to measure peri-acetabular BMD are proposed, to enable comparison between implant and patient variables in the future.Orthopaedics, Trauma Surgery and Rehabilitatio

On the Relation between Solar Activity and Clear-Sky Terrestrial Irradiance

The Mauna Loa Observatory record of direct-beam solar irradiance measurements for the years 1958-2010 is analysed to investigate the variation of clear-sky terrestrial insolation with solar activity over more than four solar cycles. The raw irradiance data exhibit a marked seasonal cycle, extended periods of lower irradiance due to emissions of volcanic aerosols, and a long-term decrease in atmospheric transmission independent of solar activity. After correcting for these effects, it is found that clear-sky terrestrial irradiance typically varies by about 0.2 +/- 0.1% over the course of the solar cycle, a change of the same order of magnitude as the variations of the total solar irradiance above the atmosphere. An investigation of changes in the clear-sky atmospheric transmission fails to find a significant trend with sunspot number. Hence there is no evidence for a yet unknown effect amplifying variations of clear-sky irradiance with solar activity.Comment: 16 pages, 7 figures, in press at Solar Physics; minor changes to the text to match final published versio

The Effects of Vitamin E Analogues α-Tocopherol and γ-Tocotrienol on the Human Osteocyte Response to Ultra-High Molecular Weight Polyethylene Wear Particles

Abstract: Polyethylene (PE) liners are a common bearing surface of orthopaedic prostheses. Wear particles of ultra-high molecular weight PE (UHMWPE) contribute to periprosthetic osteolysis, a major cause of aseptic loosening. Vitamin E is added to some PE liners to prevent oxidative degradation. Osteocytes, an important cell type for controlling both bone mineralisation and bone resorption, have been shown to respond UHMWPE particles by upregulating pro-osteoclastogenic and osteocytic osteolysis. Here, we examined the effects of the vitamin E analogues α-tocopherol and γ-tocotrienol alone or in the context of UHMWPE particles on human osteocyte gene expression and mineralisation behaviour. Human osteoblasts differentiated to an osteocyte-like stage were exposed to UHMWPE wear particles in the presence or absence of either α-Tocopherol or γ-Tocotrienol. Both α-Tocopherol and γ-Tocotrienol induced antioxidant-related gene expression. UHMWPE particles independently upregulated antioxidant gene expression, suggesting an effect of wear particles on oxidative stress. Both vitamin E analogues strongly induced OPG mRNA expression and γTocotrienol also inhibited RANKL mRNA expression, resulting in a significantly reduced RANKL:OPG mRNA ratio (p < 0.01) overall. UHMWPE particles reversed the suppressive effect of α-Tocopherol but not of γ-Tocotrienol on this pro-osteoclastogenic index. UHMWPE particles also upregulated osteocytic-osteolysis related gene expression. Vitamin E analogues alone or in combination with UHMWPE particles also resulted in upregulation of these genes. Consistent with this, both vitamin E analogues promoted calcium release from mineralised cultures of osteocyte-like cells. Our findings suggest that while vitamin E may suppress osteocyte support of osteoclastogenesis in the presence of UHMWPE particles, the antioxidant effect may induce osteocytic osteolysis, which could promote periprosthetic osteolysis. It will be important to conduct further studies of vitamin E to determine the long-term effects of its inclusion in prosthetic materials.Renee T. Ormsby, Kunihiro Hosaka, Andreas Evdokiou, Andreani Odysseos, David M. Findlay, Lucian B. Solomon, and Gerald J. Atkin

A new approach to surgical management of tibial plateau fractures

Tibial plateau fractures (TPFs) are challenging, requiring complex open reduction and internal fixation (ORIF) and are often associated with complications including surgical site infections (SSIs). In 2007, we introduced a novel management protocol to treat TPFs which consisted of an angiosome- or perforator-sparing (APS) anterolateral approach followed by unrestricted weight bearing and range of motion. The primary aim of this retrospective study was to investigate complication rates and patient outcomes associated with our new management protocol. In total, 79 TPFs treated between 2004 and 2007 through a classic anterolateral surgical approach formed the "Classic Group"; while 66 TPFS treated between 2007 and 2013 formed the "APS Group". Fracture reduction, maintenance of reduction and patient-reported outcomes were assessed. There was a clinically important improvement in the infection incidence with the APS (1.5%) versus the Classic technique (7.6%) (1/66 versus 2/79 for superficial infections; 0/66 versus 4/79 for deep infections). Despite a more aggressive rehabilitation, there was no difference in the fracture reduction over time or the functional outcomes between both groups (p > 0.05). The APS anterolateral approach improved the rate of SSIs after TPFs without compromising fracture reduction and stabilisation. We continue to use this new management approach and early unrestricted weight bearing when treating amenable TPFs.Stuart A. Callary, Claire F. Jones, Karim Kantar ... Markus P. Baker, Dominic Thewlis, Gerald J. Atkins ... et al

Evidence for osteocyte-mediated bone-matrix degradation associated with periprosthetic joint infection (PJI)

Osteomyelitis associated with periprosthetic joint infection (PJI) signals a chronic infection and the need for revision surgery. An osteomyelitic bone exhibits distinct morphological features, including evidence for osteolysis and an accelerated bone remodelling into poorly organised, poor-quality bone. In addition to immune cells, various bone cell-types have been implicated in the pathology. The present study sought to determine the types of bone-cell activities in human PJI bones. Acetabular biopsies from peri-implant bone from patients undergoing revision total hip replacement (THR) for chronic PJI (with several identified pathogens) as well as control bone from the same patients and from patients undergoing primary THR were analysed. Histological analysis confirmed that PJI bone presented increased osteoclastic activity compared to control bone. Analysis of osteocyte parameters showed no differences in osteocyte lacunar area between the acetabular bone taken from PJI patients or primary THR controls. Analysis of bone matrix composition using Masson's trichrome staining and second-harmonic generation microscopy revealed widespread lack of mature collagen, commonly surrounding osteocytes, in PJI bone. Increased expression of known collagenases, such as matrix metallopeptidase (MMP) 13, MMP1 and cathepsin K (CTSK), was measured in infected bone compared to non-infected bone. Human bone and cultured osteocyte-like cells experimentally exposed to Staphylococcus aureus exhibited strongly upregulated expression of MMP1, MMP3 and MMP13 compared to non-exposed controls. In conclusion, the study identified previously unrecognised bone-matrix changes in PJI caused by multiple organisms deriving from osteocytes. Histological examination of bone collagen composition may provide a useful adjunct diagnostic measure of PJI.R.T. Ormsby, A.R. Zelmer, D. Yang, N.J. Gunn, Y. Starczak, S.P. Kidd ... et al

A Mild Case of Autosomal Recessive Osteopetrosis Masquerading as the Dominant Form Involving Homozygous Deep Intronic Variations in the CLCN7 Gene

Published online: 26 May 2022Osteopetrosis is a heterogeneous group of rare hereditary diseases characterized by increased bone mass of poor quality. Autosomal-dominant osteopetrosis type II (ADOII) is most often caused by mutation of the CLCN7 gene leading to impaired bone resorption. Autosomal recessive osteopetrosis (ARO) is a more severe form and is frequently accompanied by additional morbidities. We report an adult male presenting with classical clinical and radiological features of ADOII. Genetic analyses showed no amino-acid-converting mutation in CLCN7 but an apparent haploinsufficiency and suppression of CLCN7 mRNA levels in peripheral blood mononuclear cells. Next generation sequencing revealed low-frequency intronic homozygous variations in CLCN7, suggesting recessive inheritance. In silico analysis of an intronic duplication c.595-120_595-86dup revealed additional binding sites for Serine- and Arginine-rich Splicing Factors (SRSF), which is predicted to impair CLCN7 expression. Quantitative backscattered electron imaging and histomorphometric analyses revealed bone tissue and material abnormalities. Giant osteoclasts were present and additionally to lamellar bone, and abundant woven bone and mineralized cartilage were observed, together with increased frequency and thickness of cement lines. Bone mineralization density distribution (BMDD) analysis revealed markedly increased average mineral content of the dense bone (CaMean T-score + 10.1) and frequency of bone with highest mineral content (CaHigh T-score + 19.6), suggesting continued mineral accumulation and lack of bone remodelling. Osteocyte lacunae sections (OLS) characteristics were unremarkable except for an unusually circular shape. Together, our findings suggest that the reduced expression of CLCN7 mRNA in osteoclasts, and possibly also osteocytes, causes poorly remodelled bone with abnormal bone matrix with high mineral content. This together with the lack of adequate bone repair mechanisms makes the material brittle and prone to fracture. While the skeletal phenotype and medical history were suggestive of ADOII, genetic analysis revealed that this is a possible mild case of ARO due to deep intronic mutation.Jochen G. Hofstaetter, Gerald J. Atkins, Hajime Kato, Masakazu Kogawa, Stéphane Blouin, Barbara M. Misof, Paul Roschger, Andreas Evdokiou, Dongqing Yang, Lucian B. Solomon, David M. Findlay, Nobuaki It