Clinical Guidance to Optimize Work Participation After Injury or Illness: The Role of Physical Therapists.

Work rehabilitation refers to the process of assisting workers to remain at work or return to work (RTW) in a safe and productive manner, while limiting the negative impact of restricted work, unemployment, and work disability. The primary purpose of this clinical practice guideline (CPG) is to systematically review available scientific evidence and provide a set of evidence-based recommendations for effective physical therapy evaluation, treatment, and management of individuals experiencing limitations in the ability to participate in work following injury or illness. J Orthop Sports Phys Ther 2021;51(8):CPG1-CPG102. doi:10.2519/jospt.2021.0303.

Elastolytic activity of cysteine cathepsins K, S, and V promotes vascular calcification.

Elastin plays an important role in maintaining blood vessel integrity. Proteolytic degradation of elastin in the vascular system promotes the development of atherosclerosis, including blood vessel calcification. Cysteine cathepsins have been implicated in this process, however, their role in disease progression and associated complications remains unclear. Here, we showed that the degradation of vascular elastin by cathepsins (Cat) K, S, and V directly stimulates the mineralization of elastin and that mineralized insoluble elastin fibers were ~25-30% more resistant to CatK, S, and V degradation when compared to native elastin. Energy dispersive X-ray spectroscopy investigations showed that insoluble elastin predigested by CatK, S, or V displayed an elemental percentage in calcium and phosphate up to 8-fold higher when compared to non-digested elastin. Cathepsin-generated elastin peptides increased the calcification of MOVAS-1 cells acting through the ERK1/2 pathway by 34-36%. We made similar observations when cathepsin-generated elastin peptides were added to ex vivo mouse aorta rings. Altogether, our data suggest that CatK-, S-, and V-mediated elastolysis directly accelerates the mineralization of the vascular matrix by the generation of nucleation points in the elastin matrix and indirectly by elastin-derived peptides stimulating the calcification by vascular smooth muscle cells. Both processes inversely protect against further extracellular matrix degradation.

Changes in Structural-Mechanical Properties and Degradability of Collagen during Aging-associated Modifications.

During aging, changes occur in the collagen network that contribute to various pathological phenotypes in the skeletal, vascular, and pulmonary systems. The aim of this study was to investigate the consequences of age-related modifications on the mechanical stability and in vitro proteolytic degradation of type I collagen. Analyzing mouse tail and bovine bone collagen, we found that collagen at both fibril and fiber levels varies in rigidity and Young's modulus due to different physiological changes, which correlate with changes in cathepsin K (CatK)-mediated degradation. A decreased susceptibility to CatK-mediated hydrolysis of fibrillar collagen was observed following mineralization and advanced glycation end product-associated modification. However, aging of bone increased CatK-mediated osteoclastic resorption by ∼27%, and negligible resorption was observed when osteoclasts were cultured on mineral-deficient bone. We observed significant differences in the excavations generated by osteoclasts and C-terminal telopeptide release during bone resorption under distinct conditions. Our data indicate that modification of collagen compromises its biomechanical integrity and affects CatK-mediated degradation both in bone and tissue, thus contributing to our understanding of extracellular matrix aging.

BMP-9 regulates the osteoblastic differentiation and calcification of vascular smooth muscle cells through an ALK1 mediated pathway.

The process of vascular calcification shares many similarities with that of physiological skeletal mineralization, and involves the deposition of hydroxyapatite crystals in arteries. However, the cellular mechanisms responsible have yet to be fully explained. Bone morphogenetic protein (BMP-9) has been shown to exert direct effects on both bone development and vascular function. In the present study, we have investigated the role of BMP-9 in vascular smooth muscle cell (VSMC) calcification. Vessel calcification in chronic kidney disease (CKD) begins pre-dialysis, with factors specific to the dialysis milieu triggering accelerated calcification. Intriguingly, BMP-9 was markedly elevated in serum from CKD children on dialysis. Furthermore, in vitro studies revealed that BMP-9 treatment causes a significant increase in VSMC calcium content, alkaline phosphatase (ALP) activity and mRNA expression of osteogenic markers. BMP-9-induced calcium deposition was significantly reduced following treatment with the ALP inhibitor 2,5-Dimethoxy-N-(quinolin-3-yl) benzenesulfonamide confirming the mediatory role of ALP in this process. The inhibition of ALK1 signalling using a soluble chimeric protein significantly reduced calcium deposition and ALP activity, confirming that BMP-9 is a physiological ALK1 ligand. Signal transduction studies revealed that BMP-9 induced Smad2, Smad3 and Smad1/5/8 phosphorylation. As these Smad proteins directly bind to Smad4 to activate target genes, siRNA studies were subsequently undertaken to examine the functional role of Smad4 in VSMC calcification. Smad4-siRNA transfection induced a significant reduction in ALP activity and calcium deposition. These novel data demonstrate that BMP-9 induces VSMC osteogenic differentiation and calcification via ALK1, Smad and ALP dependent mechanisms. This may identify new potential therapeutic strategies for clinical intervention.

Upregulation of IGF2 expression during vascular calcification.

The process of vascular calcification shares many similarities with that of skeletal mineralisation and involves the deposition of hydroxyapatite crystals in arteries and cardiac valves. However, the cellular mechanisms responsible have yet to be fully elucidated. In this study, we employed microarray analysis to demonstrate the upregulation of more than >9000 genes during the calcification of murine vascular smooth muscle cells (VSMCs), of which the most significantly, differentially expressed gene was Igf2. Following the validation of increased IGF2 expression by RT-qPCR and immunoblotting in calcifying murine VSMCs, IGF2 expression was further demonstrated in the calcified aorta of the Enpp1(-/-) mouse model of medial aortic calcification. Having confirmed that IGF1R and IGF2R were expressed in cultured murine VSMCs, cell-signalling studies in these cells revealed that IGF2 (50 ng/ml) significantly stimulated the phosphorylation of Akt and Erk1/2 (P<0.05). These results potentially indicate that IGF2 may mediate VSMC calcification via the stimulation of Erk1/2 and Akt signalling. This study suggests that the increased IGF2 expression in calcifying VSMCs may reflect the well-established prenatal role of IGF2, particularly as the osteogenic phenotypic transition of VSMCs in a calcified environment recapitulates many of the events occurring during embryonic development. A full understanding of the importance of IGF2 in this pathological process will lead to a better understanding of the aetiology of vascular calcification.

Allergic reaction to a red plastic allergy alert patient identification bracelet: implications for surgical patient safety.

We present a case of allergy to a hospital thermally-printed red plastic allergy alert bracelet in a 48 year old lady admitted to the day surgery unit. Two hours postoperatively, an intensely itchy area of erythema and oedema was seen extending from her left wrist distally to the fingers. The bracelet was removed and the rash resolved overnight without further complication. A diagnosis of contact dermatitis was made, secondary to exposure to an agent within the bracelet. We discuss the safety implications for surgical patients unable to wear an identification bracelet and the steps that may be taken to minimise the risk of harm from misidentification. We believe this to be the first documented case of an allergy to a patient identification bracelet in the medical literature.

A protective role for FGF-23 in local defence against disrupted arterial wall integrity?

Increasing interest is focusing on the role of the FGF-23/Klotho axis in mediating vascular calcification. However, the underpinning mechanisms have yet to be fully elucidated. Murine VSMCs were cultured in calcifying medium for a 21 d period. FGF-23 mRNA expression was significantly up-regulated by 7d (1.63-fold; P<0.001), with a concomitant increase in protein expression. mRNA and protein expression of both FGFR1 and Klotho were confirmed. Increased FGF-23 and Klotho protein expression was also observed in the calcified media of Enpp1(-/-) mouse aortic tissue. Reduced calcium deposition was observed in calcifying VSMCs cultured with recombinant FGF-23 (10 ng/ml; 28.1% decrease; P<0.01). Calcifying VSMCs treated with PD173074, an inhibitor of FGFR1 and FGFR3, showed significantly increased calcification (50 nM; 87.8% increase; P<0.001). FGF-23 exposure induced phosphorylation of ERK1/2. Treatment with FGF-23 in combination with PD98059, an ERK1/2 inhibitor, significantly increased VSMC calcification (10 µM; 41.3% increase; P<0.01). Use of FGF-23 may represent a novel therapeutic strategy for inhibiting vascular calcification.

Mechanisms and clinical consequences of vascular calcification.

Vascular calcification has severe clinical consequences and is considered an accurate predictor of future adverse cardiovascular events, including myocardial infarction and stroke. Previously vascular calcification was thought to be a passive process which involved the deposition of calcium and phosphate in arteries and cardiac valves. However, recent studies have shown that vascular calcification is a highly regulated, cell-mediated process similar to bone formation. In this article, we outline the current understanding of key mechanisms governing vascular calcification and highlight the clinical consequences. By understanding better the molecular pathways and genetic circuitry responsible for the pathological mineralization process novel drug targets may be identified and exploited to combat and reduce the detrimental effects of vascular calcification on human health.

Relative abundance of American badger (Taxidea taxus) and red fox (Vulpes vulpes) in landscapes with high and low rodenticide poisoning levels.

Over the past decade, extensive poisoning campaigns have been conducted in southern Saskatchewan to control Richardson's ground squirrel Spermophilus richardsonii (Sabine, 1822) populations. Such campaigns might impact on predator abundance by decreasing prey levels, and also through secondary poisoning. Using spotlighting, we investigated the relative abundance of American badgers Taxidea taxus (Schreber, 1777) and red fox Vulpes vulpes (Linnaeus, 1758) in 2 study areas with road access and crops, but with different levels of poisoning. In the study area with relatively low poisoning (19.6% of the area traversed by roads), there were 2.2 times more American badgers per km of road and 6.4 times more red foxes per km than in the study area with high poisoning (89.7% of the area). It is recommended that an Integrated Pest Management program be developed to conserve natural predators across landscapes.

Altered bone development and an increase in FGF-23 expression in Enpp1(-/-) mice.

Nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) is required for the conversion of extracellular ATP into inorganic pyrophosphate (PP(i)), a recognised inhibitor of hydroxyapatite (HA) crystal formation. A detailed phenotypic assessment of a mouse model lacking NPP1 (Enpp1(-/-)) was completed to determine the role of NPP1 in skeletal and soft tissue mineralization in juvenile and adult mice. Histopathological assessment of Enpp1(-/-) mice at 22 weeks of age revealed calcification in the aorta and kidney and ectopic cartilage formation in the joints and spine. Radiographic assessment of the hind-limb showed hyper-mineralization in the talocrural joint and hypo-mineralization in the femur and tibia. MicroCT analysis of the tibia and femur disclosed altered trabecular architecture and bone geometry at 6 and 22 weeks of age in Enpp1(-/-) mice. Trabecular number, trabecular bone volume, structure model index, trabecular and cortical thickness were all significantly reduced in tibiae and femurs from Enpp1(-/-) mice (P<0.05). Bone stiffness as determined by 3-point bending was significantly reduced in Enpp1(-/-) tibiae and femurs from 22-week-old mice (P<0.05). Circulating phosphate and calcium levels were reduced (P<0.05) in the Enpp1(-/-) null mice. Plasma levels of osteocalcin were significantly decreased at 6 weeks of age (P<0.05) in Enpp1(-/-) mice, with no differences noted at 22 weeks of age. Plasma levels of CTx (Ratlaps™) and the phosphaturic hormone FGF-23 were significantly increased in the Enpp1(-/-) mice at 22 weeks of age (P<0.05). Fgf-23 messenger RNA expression in cavarial osteoblasts was increased 12-fold in Enpp1(-/-) mice compared to controls. These results indicate that Enpp1(-/-) mice are characterized by severe disruption to the architecture and mineralization of long-bones, dysregulation of calcium/phosphate homeostasis and changes in Fgf-23 expression. We conclude that NPP1 is essential for normal bone development and control of physiological bone mineralization.

The appearance and modulation of osteocyte marker expression during calcification of vascular smooth muscle cells.

BACKGROUND: Vascular calcification is an indicator of elevated cardiovascular risk. Vascular smooth muscle cells (VSMCs), the predominant cell type involved in medial vascular calcification, can undergo phenotypic transition to both osteoblastic and chondrocytic cells within a calcifying environment. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, using in vitro VSMC calcification studies in conjunction with ex vivo analyses of a mouse model of medial calcification, we show that vascular calcification is also associated with the expression of osteocyte phenotype markers. As controls, the terminal differentiation of murine calvarial osteoblasts into osteocytes was induced in vitro in the presence of calcifying medium (containing ß-glycerophosphate and ascorbic acid), as determined by increased expression of the osteocyte markers DMP-1, E11 and sclerostin. Culture of murine aortic VSMCs under identical conditions confirmed that the calcification of these cells can also be induced in similar calcifying medium. Calcified VSMCs had increased alkaline phosphatase activity and PiT-1 expression, which are recognized markers of vascular calcification. Expression of DMP-1, E11 and sclerostin was up-regulated during VSMC calcification in vitro. Increased protein expression of E11, an early osteocyte marker, and sclerostin, expressed by more mature osteocytes was also observed in the calcified media of Enpp1(-/-) mouse aortic tissue. CONCLUSIONS/SIGNIFICANCE: This study has demonstrated the up-regulation of key osteocytic molecules during the vascular calcification process. A fuller understanding of the functional role of osteocyte formation and specifically sclerostin and E11 expression in the vascular calcification process may identify novel potential therapeutic strategies for clinical intervention.

A summary of trauma and trauma-related papers published in BJOMS during 2008-2009.

This paper provides a summary of the 49 trauma and related papers published in British Journal of Oral and Maxillofacial Surgery during the period January 2008 to December 2009. 16/49 (32%) of these publications were full length articles, which covered areas such as epidemiology, service provision, materials and operative surgery. In addition there were other articles including short communications, technical notes, letters to the editor and interesting cases. Whilst fewer full length articles were published compared to the other sub-specialties, it was reassuring to see that the studies represent all aspects of trauma. More basic science and randomized control studies relating to trauma need to be encouraged.

Evaluation of RNA-knockdown strategies for modulation of cytochrome P450 reductase activity in mouse hepatocytes.

Transgenic technologies can provide important animal models for studying drug-metabolizing enzymes. Our overall aim was to generate versatile cell and animal systems that exhibited varying levels of cytochrome P450 oxidoreductase (POR) activity, more accurately modelling the human population for pharmacological and toxicology studies. Towards this goal we evaluated RNA-interference constructs designed for use in vitro and in vivo for reducing POR activity in hepatocytes. This study clearly demonstrates that both POR protein level and reductase activity can be significantly knocked down in Hepa-1 cells in vitro, while highlighting the difficulty in predicting knockdown efficiency in transgenic animals. The high levels of embryonic lethality observed, and inability to produce multi-copy transgenic animals indicates that high levels of shRNA expression may be detrimental to embryonic development.

Prospective randomized clinical trial of the effect of needle size on pain, sample adequacy and accuracy in head and neck fine-needle aspiration cytology.

BACKGROUND: Fine-needle aspiration cytology (FNAC) is useful in the diagnosis of many conditions of the head and neck. No reported studies have investigated the optimal needle gauge in the head and neck region. METHODS: This was a prospective randomized trial of 100 patients who required FNAC performed with either a 21G or 23G needle. Discomfort was scored by patients using a visual analogue scale. Sample accuracy was assessed in patients who subsequently had excision biopsy. RESULTS: FNAC performed with a 23G needle was less painful (mean +/- SE, 1.6 +/- 1.01) than FNAC with a 21G needle (3.3 +/- 1.94; p < .001). There was no difference in sample adequacy between the 2 needle sizes (p = .59). The sensitivities and specificities of both needles were similar. CONCLUSION: Head and neck FNAC should routinely be performed with a 23G needle, resulting in less patient discomfort, and giving sample adequacy comparable to a conventional 21G needle.