Introduction: Strict maintenance of normoglycaemia with intensive insulin therapy in the critically ill surgical patients has helped to reduce morbidity and mortality by almost 50%. The notion that insulin may act independently of glucose as an anti inflammatory agent is of interest. Orthopaedist manipulate the inflammatory cascade through the practice of Damage Control Surgery. By delaying surgery they prevent a second hit in the Systemic Inflammatory Response Syndrome (SIRS) and attenuate excessive inflammation which may lead to Multiorgan Failure (MOF). An insulin infusion is a novel method of modulating the inflammatory cascade through the strict control of hyperglycaemia. The role of neutrophils and endothelium are an integral part of the inflammatory cascade. Our aim was to investigate whether insulin had an independent effect on endothelial cell activation. Aim: We hypothesise that insulin, independent of glucose, has a cytoprotective effect on the endothelium as an anti inflammatory agent. Methods: We subjected human umbilical vein endothelial cells (HUVEC) to normoxia, hypoxia and hypoxia reoxygenation to simulate trauma. These 3 groups were incubated with insulin at 0uU/ml, 10uU/ml, 50uU/ml and 100uU/ml for 24h and 48h normoxia and hypoxia. For the hypoxia reoxygenation study HUVEC were exposed to 24h of hypoxia and then 24h of reoxygenation. Proliferation of endothelial cells was measured using an MTT study. Results: Our experiment shows that hypoxia reduces HUVEC proliferation. Results show that treatment with 50uU/ml insulin for 24 hours attenuates the effect of hypoxia. This suggests that insulin at post prandial, physiological levels, in non diabetics has a cytoprotective effect on endothelial cells. This was significant in hypoxic conditions in a dose dependent manner. Conclusions: Hypoxia simulates injury and when injury occurs it activates an inflammatory response which could lead to SIRS. It has not previously been investigated how insulin acts as an anti inflammatory mediator in the control of hyperglycaemia. We can conclude that insulin may act to protect the endothelium, independent of glucose, under hypoxia and hypoxia reoxygenation conditions

Introduction: The beneficial effects of insulin in the maintenance of normoglycaemia in non-diabetic myocardial infarct and intensive care patients have recently been reported. Hyperglycaemia and neutrophilia have been shown to be independent prognostic indicators of poor outcome in the traumatised patient. The role of insulin and the maintenance of normoglycaemia in the trauma patient have as yet not been explored. We hypothesised that through the already described anti-inflammatory effects of insulin and the maintenance of normoglycaemia, that the systemic inflammatory response would be attenuated, in the injured patient. This might result in less adult respiratory distress syndrome (ARDS) and multi-organ dysfunction and therefore less morbidity and mortality in trauma patients. Materials and Methods: We used a previously validated rodent trauma model. There were 3 groups, two groups underwent bilateral femur fracture and 15% blood loss via cannulation and aspiration of the external jugular vein. The third group were anaesthetised only. The treatment group immediately receive subcutaneous insulin according to a recently identified sliding scale, and thereafter subcutaneous boluses, dependent on ½ hourly blood sugar estimations. The control groups received the same volume of normal saline ½ hourly, subcutaneously. The animals were maintained under anaesthetic for 4 hours from injury via inhaled isoflurane and oxygen. Core temperature and O2 saturations were recorded throughout. At 4 hours, each animal underwent midline laparotomy and cannulation of the IVC for blood sampling for full blood counts and lactate levels. Serum was also taken for flow cytometric analysis of neutrophil activation via respiratoy burst and CD11b levels. Broncho-alveolar lavage (BAL) was performed for neutrophil content and total protein estimation. The left lower lobe was harvested for wet-dry lung weight ratios. Results: While O2 saturations were equal throughout in both groups, respiratory rates were persistently elevated in the controls. Wet:Dry lung weight ratios (p< 0.05) and lactate levels were reduced in the insulin treated animals compared to controls. There were similiarly fewer neutrophils in the BAL specimens of the insuliln treated animals compared to injured controls (p< 0.05). Conclusions: Insulin reduces leukocyte lung sequestration in the injured animal model. This work confirms that insulin may have a role in reducing ARDS in the trauma patient, be that as an anti-inflammatory agent or anti-hyperglycaemic agent, or both, indicating that outcomes might be improved by treating hyperglycaemic trauma patients with insulin. Further work needs to done to elucidate its exact mechanism of action and role in the injured patient

Fracture neck of femur (NOF) is a significant morbidity in the elderly patient and a significant burden on the healthcare system. Surgery induces a stress response resulting in hyperglycaemia, insulin resistance, and glucose intolerance (Diabetic triad). Furthermore, fasting pre operatively establishes a catabolic state. This diabetic state can last up to 3 weeks following surgery and therefore could be associated with the morbidity of diabetes. Methods. 26 patients with fracture NOF were enrolled in this preliminary study. Exclusion criteria included diabetics. Each underwent hemiarthroplasty or Dynamic Hip Screw fixation. Pre and post operative serum glucose levels were taken. 15 patients were selected to have pre and post operative serum insulin levels because of the expensive nature of the test. Results. Normal glucose range = 4-6 mmol/l. Normal insulin range = 17.8 – 173 pmol/l. 21 of 26 patients exhibited post operative hyperglycaemia (range 5 - 16.4mmol/l). 7 of 15 patients tested for insulin remained in our pilot study where pre and post insulin levels were obtained. Insulin is a technically difficult level to take and samples are easily discarded. 6 of 7 Insulin levels showed marked elevation post operatively (range 17.5 – 595.8). Conclusion. We are able to demonstrate that fracture NOF patients exhibit a postoperative hyperglycaemia and insulin resistance. Insulin levels were significantly elevated in 6 cases and established hyperinsulinaemia was present in 50% of cases. This pilot study determines that a post operative type 2 diabetic state is induced by surgery for fracture neck of femur, perhaps exacerbated by the catabolic state of fasting. If we are able to diminish this we may be able to mitigate morbidity associated with this diabetic state. This in turn may improve the morbidity and burden on our healthcare system

Steroids are known to have an adverse effect on the blood glucose levels in diabetics. Intra-articular steroids are commonly used in Orthopaedic and Rheumatology practice. However we have failed to identify any studies to date that have been carried out on the short-term effect of intra-articular steroids in diabetics who are taking insulin. This study was carried out to establish the effects of intra-articular (IA) steroid injections on the blood glucose levels and insulin requirements for insulin dependant diabetic patients treated for a “Frozen Shoulder”. Methods: Insulin-dependant diabetic patients suffering from a “Frozen Shoulder” who were referred to our out patient clinics were recruited prospectively for this study. Each patient received 40 mg of long acting steroid plus 9 mls of 0.5% Marcain injected intra-articularly into the glenohumeral joint. They were each asked to record their subsequent blood glucose levels and insulin requirements on a form, four times a day for seven days post injection. Each patient was seen again at 6 weeks and, when appropriate, they were offered a second intra-articular injection according to the recommendations of Jacobs et al. 1. (1991). Results: Fifteen patients were recruited into the study. All patients reported a disturbance of their blood glucose control in the post injection period lasting for a variable period up to seven days. Approximately one third of patients found it necessary to increase their daily insulin requirements during the first two days after the injection. Conclusion: IA steroid injections cause disturbance of the blood glucose control in insulin dependant diabetics. Patients must be warned regarding this side effect when IA steroid injections are given

The beneficial effects of insulin in the maintenance of normoglycaemia in non-diabetic myocardial infarct and intensive care patients have recently been reported. Hyperglycaemia and neutrophilia have been shown to be independent prognostic indicators of poor outcome in the traumatised patient. The role of insulin and the maintenance of normoglycaemia in the trauma patient have as yet not been explored. We hypothesised that through the already described anti-inflammatory effects of insulin and the maintenance of normoglycaemia, that neutrophil activation and endothelial dysfunction would be attenuated, in the injured patient. This might result in less adult respiratory distress syndrome (ARDS) and multi-organ dysfunction and therefore less morbidity and mortality for the trauma patient. Materials and Methods: To study this we used a previously validated rodent trauma model. There were 2 groups, both groups underwent bilateral femur fracture and 15% blood loss via cannulation and aspiration of the external jugular vein. The treatment group immediately receive subcutaneous insulin according to a recently identified sliding scale, and thereafter subcutaneous boluses, dependent on half hourly blood sugar estimations. The control group received the same volume of normal saline half hourly, subcutaneously. The animals were maintained under anaesthetic for 4 hours from injury via inhaled halothane and oxygen. Core temperature and 0. 2. saturations were recorded throughout. At 4 hours, each animal underwent midline laparotomy and cannulation of the IVC for blood sampling for full blood counts, lactate levels and for flow cytometry to estimate neutrophil activation via respiratory burst and CD11b upregulation. Bronchoalveolar lavage (BAL) was performed for neutrophil content and total protein estimation. The left lower lobe was harvested for wet-dry lung weight ratios. Results: While 0. 2. saturations were equal throughout in both groups, respiratory rates were persistently elevated in the controls. Wet:Dry lung ratios and lactate levels were reduced in the insulin treated animals compared to controls. There were similarly fewer neutrophils in the BAL specimens of the insulin treated animals (p< 0.05). Conclusions: Insulin reduces leukocyte lung sequestration in the injured animal model. This work confirms that insulin may have a role in reducing ARDS in the trauma patient, be that as an anti-inflammatory agent or anti-hyperglycaemic agent, or both, indicating that outcomes might be improved by treating hyperglycaemic trauma patients with insulin. Further work needs to be done to elucidate its exact mechanism of action and role in the injured patient

Aims. Hip fractures pose a significant burden on the healthcare system. Hyperglycaemia and a state of Type 2 diabetes exists post operatively. Being normoglycaemic has well documented benefits. Pre operative carbohydrate loading has been shown to have two good effects. It decrease hyperglycaemia post operatively and allows the patient to undergo less strict fasting protocols. Insulin resistance to date has not been examined in these patients and this was determined using a validated formula (HOMA/IR). Methods. Three trauma hospitals were enrolled and patients with hip fractures requiring operative fixation were enlisted. Exclusion criteria: diabetic patients and inability to imbibe. 100 neck of femur fractures were examined. 46 patients were fasted normally. 32 test patients were given a carbohydrate rich drink pre operatively the night before surgery and in the morning up to 2 hours prior to surgery. 22 patients were excluded. Serum random glucose and insulin levels were taken on admission. Fasting serum glucose and insulin levels were taken on day one post operatively. Results. Control vs Trial average age: 82y and 75y. Admission glucose levels for Control vs Pre Op Loading: 6.5 vs 6.77 mmol/l. The average post operative Control vs Pre Op Loading: Glucose: 7.59 mmol/l vs 6.23mmol/. HOMA/IR in the control vs Pre Op loading group were: 1.86 and 1.2 compared to Post Op readings of 12 and 2. Paired T Test shows that there is significant decrease in hyperglycaemia and insulin resistance (p< 0.05). Conclusions. Pre operative carbohydrate loading leads to a decrease in hyperglycaemia and insulin resistance after surgery for hip fractures. Furthermore, patients are permitted a more liberal fasting regime leading to improved patient well being and less anxiety. The morbidity associated with a hyperglycaemic diabetic state is well documented and avoidance of this may lead to a decreased burden on the healthcare system

Aims. Myokine developmental endothelial locus-1 (DEL-1) has been documented to alleviate inflammation and endoplasmic reticulum (ER) stress in various cell types. However, the effects of DEL-1 on inflammation, ER stress, and apoptosis in tenocytes remain unclear. Methods. Human primary tenocytes were cultured in palmitate (400 μM) and palmitate plus DEL-1 (0 to 2 μg/ml) conditions for 24 hours. The expression levels of ER stress markers and cleaved caspase 3, as well as phosphorylated 5' adenosine monophosphate-activated protein kinase (AMPK) and autophagy markers, were assessed by Western blotting. Autophagosome formation was measured by staining with monodansylcadaverine, and apoptosis was determined by cell viability assay and caspase 3 activity assay. Results. We found that treatment with DEL-1 suppressed palmitate-induced inflammation, ER stress, and apoptosis in human primary tenocytes. DEL-1 treatment augmented LC3 conversion and p62 degradation as well as AMPK phosphorylation. Moreover, small interfering RNA for AMPK or 3-methyladenine (3-MA), an autophagy inhibitor, abolished the suppressive effects of DEL-1 on inflammation, ER stress, and apoptosis in tenocytes. Similar to DEL-1, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMPK, also attenuated palmitate-induced inflammation, ER stress, and apoptosis in tenocytes, which 3-MA reversed. Conclusion. These results revealed that DEL-1 suppresses inflammation and ER stress, thereby attenuating tenocyte apoptosis through AMPK/autophagy-mediated signalling. Thus, regular exercise or administration of DEL-1 may directly contribute to improving tendinitis exacerbated by obesity and insulin resistance. Cite this article: Bone Joint Res 2022;11(12):854–861

Aims. Glucose-insulin-potassium (GIK) is protective following cardiac myocyte ischaemia-reperfusion (IR) injury, however the role of GIK in protecting skeletal muscle from IR injury has not been evaluated. Given the similar mechanisms by which cardiac and skeletal muscle sustain an IR injury, we hypothesized that GIK would similarly protect skeletal muscle viability. Methods. A total of 20 C57BL/6 male mice (10 control, 10 GIK) sustained a hindlimb IR injury using a 2.5-hour rubber band tourniquet. Immediately prior to tourniquet placement, a subcutaneous osmotic pump was placed which infused control mice with saline (0.9% sodium chloride) and treated mice with GIK (40% glucose, 50 U/l insulin, 80 mEq/L KCl, pH 4.5) at a rate of 16 µl/hr for 26.5 hours. At 24 hours following tourniquet removal, bilateral (tourniqueted and non-tourniqueted) gastrocnemius muscles were triphenyltetrazolium chloride (TTC)-stained to quantify percentage muscle viability. Bilateral peroneal muscles were used for gene expression analysis, serum creatinine and creatine kinase activity were measured, and a validated murine ethogram was used to quantify pain before euthanasia. Results. GIK treatment resulted in a significant protection of skeletal muscle with increased viability (GIK 22.07% (SD 15.48%)) compared to saline control (control 3.14% (SD 3.29%)) (p = 0.005). Additionally, GIK led to a statistically significant reduction in gene expression markers of cell death (CASP3, p < 0.001) and inflammation (NOS2, p < 0.001; IGF1, p = 0.007; IL-1β, p = 0.002; TNFα, p = 0.012), and a significant reduction in serum creatine kinase (p = 0.004) and creatinine (p < 0.001). GIK led to a significant reduction in IR-related pain (p = 0.030). Conclusion. Systemic GIK infusion during and after limb ischaemia protects murine skeletal muscle from cell death, kidneys from reperfusion metabolites, and reduces pain by reducing post-ischaemic inflammation. Cite this article: Bone Joint Res 2023;12(3):212–218

Aims: Immature articular cartilage has a different celularity from mature articular cartilage. Thus, the healing response may be different between these tissues. In this study, we investigated the role of IGF-I in full-thickness articular cartilage defects between immature and mature rabbits. Methods: This study used 36 immature and 36 mature New Zealand rabbits. Full-thickness articular cartilage defects in the medial femoral condyle were created. Spontaneous evolution occurred in 36 animals (18 immature and 18 mature). The other 36 animals were treated with a locally administrated IGF-I. The animals were killed in groups of eight at 4th, 8th and 12th weeks. Macroscopic, histopathologic and biochemical results were evaluated and analyzed statistically. Results: Serum IGF-I levels were signiþcantly higher in the immature group than the mature group (p< 0.001). Serum IGFBP-3 levels were signiþcantly higher in the mature group than the immature group (p< 0.05). Immunuhistochemical investigation showed chondrcyte proliferation in both groups, but duration of cell proliferation and healing process were shorter in the immature groups. The cell morphology was different between the groups. Local IGF-I treated groups had better histological scores than the control groups at all weeks (p< 0.001). Conclusions: The healing response in mature and immature cartilage were similar but the duration of this healing process was shorter in the immature group and repairing cell morphology was similar to that of the normal chondrocyte.

Nitric oxide is a free radical which in vivo is solely produced during the conversion of the amino acid arginine into citrulline by nitric oxide synthase enzymes. Recently, the importance of nitric oxide on inflammation and bone metabolism has been investigated. However, the knowledge regarding possible in vitro effects of arginine supplementation on chondrogenic differentiation is limited. ATDC5, a cell line which is derived from mouse teratocarcinoma cells and which is characterized as chondrogenic cell line, were proliferated in Dulbecco's Modified Eagle Medium (DMEM)/F12 and subsequently differentiated in proliferation medium supplemented with insulin, transferrin and sodium-selenite and where arginine was added in four different concentrations (0, 7.5, 15 and 30 mM). Samples were harvested after 7 or 10 days and were stored at −80 °C for subsequent RNA isolation for qPCR analysis. To determine chondrogenic differentiation, Alcian Blue staining was performed to stain the proteoglycan aggrecan, which is secreted by differentiated ATDC5 cells. All measurements were performed in triplo. Alcian Blue staining showed a qualitative increase of proteoglycan aggrecan secretion in differentiated ATDC5 cells after treatment with 7 and 15 mM arginine, with additional increased expression of ColII, ColX, Bmp4 and Bmp6. Treatment with 30 mM arginine inhibited chondrogenic differentiation and expression of aforementioned genes, however, Cox-2 and Vegfa gene expression were increased in these samples. Bmp7 was not significantly expressed in any experimental condition. The obtained results are suggestive for a dose-dependent effect of arginine supplementation on chondrogenic differentiation and associated gene expression, with 7.5 and 15 mM as most optimal concentrations and implications for apoptosis after incubation with 30 mM arginine. A future recommendation would be to investigate the effects of citrulline in a similar experiment, as this shows even more promising results to enhance the nitric oxide metabolism in sepsis and bone healing

The enthesis is a specialised zonal tissue interface between tendon and bone, essential for adequate force transmission and composed by four distinct zones (tendon, fibrocartilage, mineralized fibrocartilage and bone). After injury, the native structure is often not re-established and a mechanically weaker fibrovascular scar is formed. Traditionally used monotherapies have failed to be effective, posing the need for multi-cargo localized delivery vehicles. We hypothesize that multilayer collagen-based scaffolds can serve as delivery vehicles for specific bioactive molecules with tenogenic, chondrogenic and osteogenic potential to enhance the functional regeneration of the enthesis. Three-layer scaffolds composed by a tendon-like layer of collagen type I, a cartilage-like layer of collagen type II and a bone-like layer of collagen type I and hydroxyapatite were fabricated by an iterative layering freeze-drying technique. The scaffolds were cross-linked with varying concentration of 4-arm polyethylene glycol (4s-PEG) and the biological and mechanical properties were assessed. Each layer was functionalized with platelet-derived growth factor, insulin growth factor, heparan sulfate or bone morphogenetic protein 7 and their tenogenic, chondrogenic and osteogenic potential on bone-marrow derived stem cells was investigated in vitro. Scaffolds cross-linked with 1 mM 4s-PEG showed 60% free amines reduction respect to non-cross-linked scaffolds, were stable in collagenase over 24 hours and had a compression modulus of 30 kPa. The bioactive molecules had a sustained release profile (approximately 50 ng/mL) over 5 days as a function of cross-linking. Preliminary in vitro studies confirmed the chondrogenic potential of heparin sulfate and insulin growth factor by the increase of proteoglycans

Introduction: Fasting overnight NPO (Nulla per os) has been routine before surgery for the past century. The practice was previously designed to reduce the risk of pulmonary aspiration on induction. However this practice has been challenged over the recent years and is changing anaesthetic practices are now more liberal. There are many new concepts aimed at improving patient outcome by regulating metabolic, endocrine, inflammatory and immune responses. This combined with better patient satisfaction and lower anxiety has led to research in this area. Overnight fasting can induce post operative insulin resistance. Insulin resistance is related to infectious morbidity and increased hospital length of stay (HLOS). Previously this concept was only important in diabetic patients. Surgery places the body under metabolic stress and even a short period of fasting will change the metabolic state of the patient. Indeed physical trauma can cause a triad known as the “diabetes of injury”: insulin resistance, hyperglycaemia and glucose intolerance. Preparation for surgery by maintaining a fasted state and catabolic metabolism may have deleterious consequences for the patient. Previous studies on elective patients has shown that pre operative carbohydrate loading can reduce insulin resistance and mitigate the inflammatory response by immunomodulation. It has not previously been shown to have an effect in the hip fracture population. This particular group of patients are often elderly and require medical and anaesthetic work up. This delay can mean that the patient is kept fasting for prolonged periods and often overnight. Methods: With full ethical approval at Connolly Hospital we prospectively randomised all femoral and hip fractures for surgery. We excluded diabetics and pregnant women from the study. A high carbohydrate drink called Nutritia Pre Op was selected. Random serum glucose was taken on admission. Patients were randomised and selected for the trial by hidden ballot. Anaesthetic approval was sought for each case. We compared our standard treatment for hip and femoral fractures of strict NPO prior to surgery versus giving patients the Pre Op drink. Each carton was 200ml and up to 4 were given the night before surgery. In the morning the patients were given another 2 drinks. There was a strict minimum 2 hour NPO period before leaving the ward. Glucose levels were then taken at 1 and 12 hours post operatively to assess whether hyperglycaemia was present. As per laboratory values a normoglycaemia was considered as 4–6mmol/l. Gender, age, type of operation, HLOS, complications and re-admissions were noted. Results: In total 17 patients were enrolled in the study. Group A had 9 patients and were kept NPO as the control group. Group B had 8 patients enlisted in the Pre Op Drink group. In group A, 6 of 9 (67%) patients had a post operative hyperglycaemia. Average age in group A was 79.6 years with an average HLOS of 15.8 days. 4 patients between them required 8 readmissions over a 3 month post operative period. Group B showed 2 out of 8 (25%) patients had a hyperglycaemia. They had an average age of 69 years with an average HLOS of 11.75 days. 4 patients required 4 readmissions. Conclusions: Pre Op high carbohydrate drinks significantly decrease post operative hyperglycaemia as per the laboratory ranges. This in turn supports that it decrease insulin resistance by preparing the body for surgery in a fed state. In the same way that one would not prepare for a marathon by fasting 24 hours before hand so the body recognizes that the surgical stress is not best dealt with when in a fasted state. The control group had twice as many readmissions and a longer HLOS. Previous studies show that there is decreased anxiety, thirst and hunger both pre and post operatively. We have shown that this is a safe drink to give and that post operative hyperglycaemia was better controlled

Dysglycemia in the post-operative period has been associated with increased rates of infection following total joint arthroplasty. Additionally, patients without clinical diagnosis of diabetes with hemoglobin A1c% values between 5.7% and 6.4% have been shown to be dysglycemic in the peri-operative period. This study examines the influence of post-operative blood glucose management on rates of re-operation for infection in patients undergoing total joint arthroplasty in diabetic, and clinically non-diabetic patients. We performed a retrospective review of prospectively collected data, for all primary, elective total hip and total knee arthroplasties performed at The Ottawa Hospital between April 2010 and October 2017. Kaplan-Meier survivorship, and mutivarient regression analysis were used to determine predictors of infection based on pre-operative diabetes status, HbA1c%, and post-operative insulin management. 4159 joints met inclusion criteria. Patients with HbA1c 5.7–6.4% had lower rate of revision for infection if they received post-operative blood glucose management (0.80%), vs without glucose management (1.20%). Kaplan-Meier survivorship analysis showed this difference to be insignificant (p=0.23). Patients with DM1 had statistically worse survivorship when compared to other groups (p=0.010). Patients with undiagnosed perioperative dysglycemia may be at a greater predisposition for developing infection, requiring re-operation, following total joint arthroplasty. This study may be underpowered due to overall low rates of revision. More rigorous peri-operative glucose management strategies may be required for patients, who otherwise receive no glycemic management outside of hospital. This is more pertinent with trends towards decreasing post-operative lengths-of-stay

There is nothing going to ruin your day like a complication after shoulder arthroplasty, either hemiarthroplasty (HA) anatomical (TSA) or reverse arthroplasty (RTSA). While complications are fortunately uncommon with anatomical shoulder arthroplasty (approximately 8% but as high as 40%), the complication rate for RTSA has been reported as high as 70%. Most complications are multifactorial and cannot all be blamed on the patient. Basically you do not want to operate upon a young patient who is an insulin dependent diabetic, has an ASA of 3 or 4, who smokes, has HIV disease and has a BMI over 40. The most common predictors of failure are determined by the indication for surgery, the type of implant used and the skill of the surgeon. The major risk factors for HA are eccentric glenoids, young age and rotator cuff failure. The biggest risk factors for TSA are metal backed glenoid components, younger age of the patient, rotator cuff pathology and insufficient glenoid bone. The major risk factors for RTSA are the type of component used (Grammont type versus lateral center of rotation designs) and the indication for surgery. Infection risks include previous infected arthroplasty, previous joint infection, immunosuppression (e.g. steroid use, insulin dependent diabetes, HIV disease), ASA 3 or 4 and higher BMI (i.e. over 40). Not all of these risk factors can be prevented in patients but informed consent is critical to the patient understanding the potential outcomes of their surgery

Summary. Arginine supplementation is helpful in treatment of osteoporosis. Introduction. Nitric oxide (NO) is a short-lived free radical involved in several biological processes as a bioregulator and as a second messenger. It inhibits osteoclastic bone resorption in vitro and regulates bone remodeling. Zolendronic acid has been established as a treatment for post menopausal osteoporosis. Study was done to compare the efficacy of Nitic oxide donor (L-arginine) with that of Zolendronic acid for the treatment of osteoporosis. Method. The study was not designed to compare these two drugs against a placebo, because the beneficial effects of Zolendronic acid in treatment of osteoporosis are well established. Institutional Review Board approvals were obtained. One hundred patients of osteoporosis having T score of −2.5 or more, were randomised to receive L-arginine) or Zolendronic acid. All patients received 1.0 g of calcium and 400 IU of vitamin D supplementation per day. In addition Group I patients received L-arginine (2 gm.) per day while Group II patients received zoledronic acid 5 mg i.v. over 15 min. Patient were followed at regular intervals clinically, by biochemical investigations and at one year for DEXA scan. Results. Patients in both groups improved clinically and bio-chemically over one year period. T score on DEXA scan at one year showed improvement in bone density. Average pretreatment T score was −3.65 in group I and −3.52 in group II. At one year followup average T score was −2.9 in group I and −2.6 in group II. Difference was not statistically significant. Discussion. Oral administration of L-arginine in pharmacological doses induces growth hormone and insulin like growth factor-1 responses and stimulates nitric oxide synthesis. Growth hormone and insulin like growth factor-1 are important mediator of bone turnover and osteoblastic bone formation. While nitric oxide is potent inhibitor of osteoclastic bone resorption because of this dual effect on physiological regulator of bone remodeling. L-arginine could potentially increase bone formation over bone resorption and consequently increase bone mass. Oral supplementation of L-arginine may be novel strategy in prevention and treatment of osteoporosis

Introduction: Surgery may cause a metabolic response leading to a diabetic state characterised by hyperglycaemia, insulin resistance and glucose intolerance. Metabolic stress may be worsened by the practice of Nulla Per Os (NPO). Hip fracture patients are often subjected to fasting for extended periods. We hypothesise that a pre operative high carbohydrate drink permitted prior to surgery would mitigate the post operative diabetic state. Methods: Ethical and Anaesthetic approval were obtained. 40 patients with hip fractures were enrolled over 4 months at Mayo General Hospital and were randomized to two groups. 20 were enrolled into Group A: control traditional NPO and Group B: Carbohydrate group. Data collection: Glucose and insulin serum levels were recorded regularly at: preadmission, post op and post op days 1 & 5; and weeks 2,3 & 6. Drink protocol: 800mls before midnight and 400mls on the morning of surgery. Exclusion criteria included diabetics and pregnancy. Hospital length of stay (HLOS), morbidity and readmissions were noted. Result: Average age Group A: X Group B:Y. Hyperglycaemia post operatively noted in 70% of Group A vs 30% in Group B. Hyperinsulinaemia postoperatively noted in 75% of Group A vs 28% Group B. Group A and B had similar HLOS and post operative morbidity. However, we noted a higher readmission rate 45% in Group A. Conclusion: Preoperative Carbohydrate loading significantly decreases post operative hyperglycemia and hyper insulinamia. This may show that converting a patient from fasted to a fed state prior to the insult of surgery prevents the patient entering a diabetic state and avoiding morbidity associated with same

Breast and other cancers commonly metastasize to bone to cause bone destruction, pain, fractures hypercalcemia and muscle weakness. Recently, we described a specific molecular mechanism by which bone-derived transforming growth factor (TGF)-beta, released as a consequence of tumor-induced bone destruction causes muscle dysfunction, before the loss of muscle mass. Circulating TGF-beta induces oxidation of the ryanodine receptor (RYR1) on the sarcoplasmic reticulum of skeletal muscle to induce calcium leak and muscle weakness. Blocking TGF-beta, or its release from bone (with bisphosphonates), preventing oxidation of or stabilizing RyR1 all prevented muscle weakness in mouse models of breast cancer bone metastases. In addition to these effects on skeletal muscle, circulating TGF-beta may act on beta cells of the pancreas to impair insulin secretion and result in glucose intolerance. These and other potential systemic effects of TGF-beta released from the tumor-bone microenvironment or from cancer treatment-induced bone destruction implicate bone as a major source of systemic effects of cancer and cancer treatment. Therapy to block the systemic effects of the bone microenvironment will improve morbidity associated with bone metastases and cancer treatment

Engineered cartilage is poorly organized and fails to recapitulate physiologic organization in a hyaline upper and a mineralizing bottom zone deemed important for proper function. Objective was to grow bizonal human cartilage constructs in which in vivo mineralization is self-restricted to the bottom zone. Self-assembling biomaterial-free cell discs were generated from mesenchymal stroma cells and allowed to accumulate proteoglycans and collagen-type II over 3 weeks. In vitro mineralization of the cell discs with four mineralization media for up to 8 weeks showed that calcification was supported in all media containing ß-glycerophosphate. However, proteoglycans were retained only in media containing insulin. Bizonal cartilage constructs were made from 3-week non-mineralized cell discs overlaid with chondrocyte-seeded starPEG-heparin hydrogel or with a fibrin-gel layer to select the best design for upper zone development. Freshly prepared zonal constructs were implanted into subcutaneous pouches of immuno-deficient mice to compare in vivo development. After 6 weeks in vivo, both construct types were rich in collagen-type II in the upper zone and contained a mineralized bottom zone. However, solely for starPEG constructs, tissue volume of the upper zone remained high and alkaline phosphatase, alizarin red, and collagen-type X staining were restricted to the bottom zone. StarPEG zonal constructs were superior to fibrin constructs due to self-restriction of mineralization and hypertrophic markers to the bottom zone. This innovative design of bizonal constructs offers the successful generation of an organized cartilage resembling the native cartilage with the chance for immediate use of autogenous chondrocytes in a one-step surgical joint intervention

Introduction and Aims: To deliver osteogenic cells into bone defects, the crucial steps are cell attachment and migration in cell-delivery biomaterials. The aim of this study was to examine whether complexes comprised of vitronectin (VN), insulin growth factors (IGFs) and insulin growth factor binding proteins (IGFBPs) could enhance human osteoblasts attachment, especially cell migration in three-dimensional (3-D) culture. Method: Human osteoblasts derived from alveolar bone chips (passage 4–10) and established human osteoblast cell line SaOS-2 were used. These cells were seeded on scaffolds of type I collagen sponges and poly glycolic acid (PGA) (approx. one millimetre thick, porous structure), which had been coated with VN +/− IGF-I +/− IGFBP-3. Cell attachment and migration were evaluated by cell counting, confocal microscopy, and scanning electron microscopy. Results: The number of attached human osteoblasts was significantly higher in wells in which pre-bound VN was coated on the polystyrene culture dish or on type I collagen sponges. However, no significant difference of cell attachment was observed when growth factors were bound to these surfaces in the presence of VN. In the two scaffold materials examined, greater cell attachment was found in type I collagen sponges compared to PGA scaffolds. However, coating the scaffolds with complexes comprised of VN + IGF-I or VN + IGFBP-5 + IGF-I enhanced cell attachment on PGA. Moreover, the presence of vitronectin + IGF-I + IGFBP-5 resulted in significantly greater osteoblast migration into deep pore areas as compared to untreated scaffolds or scaffolds treated with different combinations of the VN +/− IGF +/− IGFBP-5. Conclusion: Complexes of VN + IGFBP-5 + IGF-I enhance the attachment and migration of human osteoblast in three-dimensional culture, which implies that this complex has potential application for use in surface modification of biomaterials for tissue reconstruction

Aims

To map literature on prognostic factors related to outcomes of revision total knee arthroplasty (rTKA), to identify extensively studied factors and to guide future research into what domains need further exploration.