Robust cellular bioenergetics is vital in the energy-demanding process of maintaining matrix homeostasis in the intervertebral disc. Age-related decline in disc cellular bioenergetics is hypothesised to contribute to the matrix homeostatic perturbation observed in intervertebral disc degeneration. The present study aimed to measure how ageing impacted disc cell mitochondria and bioenergetics. Age-related changes measured included matrix content and cellularity in disc tissue, as well as matrix synthesis, cell proliferation and senescence markers in cell cultures derived from annulus fibrosus (AF) and nucleus pulposus (NP) isolated from the discs of young (6-9 months) and older (36-50 months) New Zealand White rabbits. Cellular bioenergetic parameters were measured using a Seahorse XFe96 Analyzer, in addition to quantitating mitochondrial morphological changes and membrane potential. Ageing reduced mitochondrial number and membrane potential in both cell types. Also, it significantly reduced glycolytic capacity, mitochondrial reserve capacity, maximum aerobic capacity and non-glucose-dependent respiration in NP. Moreover, NP cells exhibited age-related decline in matrix synthesis and reduced cellularity in older tissues. Despite a lack of changes in mitochondrial respiration with age, AF cells showed an increase in glycolysis and altered matrix production. While previous studies report age-related matrix degenerative changes in disc cells, the present study revealed, for the first time, that ageing affected mitochondrial number and function, particularly in NP cells. Consequently, age-related bioenergetic changes may contribute to the functional alterations in aged NP cells that underlie disc degeneration.
PurposePaediatric femur fractures are commonly encountered and often successfully managed with spica casting. Despite spica casting’s long history there is little formal guidance for optimal outcomes and no consolidation of existing literature. The purpose of this study is to review the available literature regarding the use of spica casting for the management of paediatric diaphyseal femur fractures.MethodsThe PubMed database was queried for all research articles including the phrase “spica”. A total of 788 abstracts were reviewed for relevance to the current study. Data was extracted from all available research studies which specified tolerance for fracture angulation or shortening in the cast. Additionally, all articles describing alternative materials, methods for spica application, and complications of spica casting were reviewed.ResultsIn all, 106 articles were found relevant to the management of diaphyseal femur fractures in the paediatric population. The aggregated, accepted fracture shortening decreased from 16 mm to 18 mm before age ten years to 12 mm to 14 mm after puberty. Aggregated, accepted angulation decreased from 14° to 16° varus/valgus and 18° to 22° pro/recurvatum before age two years, to 6° to 8° and 10° to 12° by puberty, respectively. The overall reported complication rate was 19.6%, with the most common complication being skin compromise in 8.2% of patients, followed by unacceptable angulation at the fracture site in 4.2% of patients and excessive limb shortening in 1.9% of patients.ConclusionThis article reviews the available spica casting literature and compiles the available data. Spica casting offers a safe, effective means for definitive management of paediatric diaphyseal femur fractures. Future research identifying the rate and pattern of remodelling as it relates to angulation and shortening at various patient ages, particularly beyond the aforementioned norms, would be valuable to identify true biological tolerances versus accepted expert opinion.Level of evidence Level IIReview of level II evidence
NF-κB signaling mediates catabolic and inflammatory responses to inflammatory and mechanical stimulation but does not mediate the decrease in matrix synthesis under combined harmful stimulation. Identification of key control points in the cellular responses to inflammatory and mechanical stimuli will facilitate rational design of exercise-based therapies and facilitate synergistic treatments of novel biochemical treatments with rehabilitation regimens.
Purpose Allografts are frequently use for ligamentous reconstruction at the knee. In the United States, tissue donation and distribution are highly regulated processes with thorough oversight from private and government entities. Allograft is widely available in the United States and allograft procurement is a large industry with varying procurement, sterilization, processing, and distribution procedures. It is important to understand allograft regulation and processing which may affect graft mechanical properties and biological graft integration. Methods English-language literature, United States government and regulatory agency statues pertaining to allograft procurement, distribution, and usage were reviewed and the findings summarized. Results During the processing of allograft, multiple factors including sterilization procedures, irradiation, storage conditions, and graft type all affect the biomechanical properties of the allograft tissue. Biological incorporation and ligamentization of allograft does occur, but at a slower rate compared with autograft. For ligamentous reconstruction around the knee, allograft offers shorter operative time, no donor-site morbidity, but has shown an increased risk for graft failure compared to autograft. Conclusion This article reviews the regulations on graft tissue within the United States, factors affecting the biomechanics of allograft tissue, differences in allograft tissue choices, and the use of allograft for anterior cruciate ligament reconstruction and multiligamentous knee injury reconstruction.
Genetic alterations of ␣-actinin-4 can cause podocyte injury through multiple mechanisms. Although a mechanism involving gain-of-␣-actinin-4 function was well described and is responsible for a dominantly inherited form of human focal segmental glomerulosclerosis (FSGS), evidence supporting mechanisms involving loss-of-␣-actinin-4 function in human glomerular diseases remains elusive. Here we show that ␣-actinin-4 deficiency occurs in multiple human primary glomerulopathies including sporadic FSGS, minimal change disease, and IgA nephropathy. Furthermore, we identify a close correlation between the levels of ␣-actinin-4 and CLP36, which form a complex in normal podocytes, in human glomerular diseases. siRNA-mediated depletion of ␣-actinin-4 in human podocytes resulted in a marked reduction of the CLP36 level. Additionally, two FSGS-associated ␣-actinin-4 mutations (R310Q and Q348R) inhibited the complex formation between ␣-actinin-4 and CLP36. Inhibition of the ␣-actinin-4-CLP36 complex, like loss of ␣-actinin-4, markedly reduced the level of CLP36 in podocytes. Finally, reduction of the CLP36 level or disruption of the ␣-actinin-4-CLP36 complex significantly inhibited RhoA activity and generation of traction force in podocytes. Our studies reveal a critical role of the ␣-actinin-4-CLP36 complex in podocytes and provide an explanation as to how ␣-actinin-4 deficiency or mutations found in human patients could contribute to podocyte defects and glomerular failure through a lossof-function mechanism.Chronic and end stage kidney diseases, which are frequently caused by defects in glomerular filtration barrier function, have become a major global health problem. Although many factors can contribute to the development and progression of human glomerulopathies, genetic defects play important roles in the disease processes (1-6). Elucidation of how genetic alterations contribute to glomerular defects is therefore critical for understanding the molecular mechanisms underlying the development and progression of human glomerulopathies.The glomerular filtration barrier is composed of an endothelium, a glomerular basement membrane, and a layer of podocytes building the slit diaphragm for filtration with their interdigitating foot processes. Although genetic alterations can cause defects in any of the three layers of the glomerular filtration barrier, podocytes appear to be a frequent target of genetic alterations in glomerulopathies (3, 4, 7-14). ␣-Actinin-4 is a member of the actinin protein family that consists of an actinbinding domain in the N terminus, four spectrin-like repeats in the central region, and two EF-hand motifs in the C terminus (15). Although both ␣-actinin-1 and -4 are expressed in mouse podocytes, ␣-actinin-4 is the sole member of the actinin family expressed in human podocytes (16). ␣-Actinin-4 is widely expressed in mammalian tissues and organs. However, despite the widespread expression, podocytes appear to be the primary site of manifestations of diseases induced by genetic alterations of ACTN4 (16,...
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