Evaluation of the quality of fit of flexible bolus material created using 3D printing technology.

AIMS: To retrospectively evaluate the quality of fit of 3D printed bolus over four different treatment sites to determine whether certain sites favor a 3D printed approach and if the quality of fit changes over the course of treatment. MATERIALS AND METHODS: A retrospective analysis of the first 60 cases treated using 3D printed bolus in our radiotherapy center was undertaken. All boluses were printed using flexible thermoplastic polyurethane (TPU) material. We developed a system of rating the quality of fit using four quality categories. The analysis of 60 patients consisted of a review of a total 627 treatment fractions for head and neck (H&N), scalp, pelvis, and extremity treatment sites. RESULTS: Out of 627 fractions evaluated, 75.1% were rated either "good" or "excellent", 20.6% were rated as "acceptable" and 4.3% were rated "poor". H&N, scalp, and extremity treatment regions were found to favor a 3D printed approach. However, pelvis cases had a higher proportion of "acceptable" and "poor" ratings. Trend analysis showed no notable change in the quality of 3D printed bolus fit over the course of treatment, except for pelvis cases which tended to change categories more than other treatment sites. CONCLUSION: This evaluation demonstrates that 3D printed bolus, created using semi-flexible materials such as TPU, is an effective and practical bolus choice for radiotherapy. In particular, using a 3D printed approach for H&N, scalp, and extremities was found to have a highly conformal fit.

Association of follow-up imaging frequency with temporal incidence and patterns of distant failure following (chemo) radiotherapy for HPV related oropharyngeal cancer.

OBJECTIVES: Emerging data supports radical intent therapy for oligometastatic (OM) relapsed human papilloma virus (HPV+) related oropharyngeal cancer (OPC). We assess the association of follow-up imaging frequency amongst HPV + OPC, with temporal and spatial patterns of distant relapse, to inform rationalisation of routine post-treatment imaging. MATERIALS AND METHODS: A retrospective single centre cohort study was carried out of consecutive HPV + OPC patients treated with radical intent (chemo)radiotherapy ((CT)RT) between 2011 and 2019. OM state was defined as ≤ 5 metastasis, none larger than 3 cm (OMs) or, if interval from last negative surveillance imaging > 6-months, then ≤ 10 metastasis, none larger than 5 cm, (OMp). Patients not meeting OMs / OMp criteria were deemed to have incurable diffuse metastatic disease (DMdiffuse). RESULTS: 793 HPV-OPC patients were identified with median follow-up 3.15years (range 0.2-8.9). 52 (6.6 %) patients had radiologically identified DM at first failure and were considered for analysis. The median time to recurrence was 15.1 months (range: 2.6-63 months). 87 % of distant metastasis (DM) occurred in the first two years after treatment. Twenty-seven (52 %) patients had OM (OMs or OMp) at time of failure, with 31 % having OMs. The median time from completion of treatment to diagnosis of DMdiffuse vs OM was 22.2 months (range: 2.6-63.1 months) vs 11.6 months (range: 3.5-32.5 months). The probability of being diagnosed with OM vs DMdiffuse increased with reducing interval from last negative surveillance scan to imaging identifying DM (≤6 months 88.9 %, 7-12 months 71.4 %, 13-24 months 35 %, > 24 months 22.2 %). CONCLUSION: We demonstrate that a reduced interval between last negative imaging and subsequent radiological diagnosis of DM is associated with increased likelihood of identification of OM disease. Consideration of increased frequency of surveillance imaging during the first two years of follow up is supported, particularly for patients at high risk of distant failure.

Exploring Hypoxia in Prostate Cancer With T2-weighted Magnetic Resonance Imaging Radiomics and Pimonidazole Scoring.

BACKGROUND/AIM: Radiomics involves high throughput extraction of mineable precise quantitative imaging features that serve as non-invasive prognostic or predictive biomarkers. High levels of hypoxia are associated with a poorer prognosis in prostate cancer and limit radiation therapy efficacy. Most patients with prostate cancer undergo magnetic resonance imaging (MRI) as a part of their diagnostics, and T2 imaging is the most utilised imaging method. The aim of this study was to determine whether hypoxia in prostate tumors could be identified using a radiomics model extracted from T2-weighted MR images. MATERIALS AND METHODS: Eighty eight intermediate or high-risk prostate cancer patients were evaluated. Prior to radical prostatectomy, all patients received pimonidazole (PIMO). PIMO hypoxic scores were assigned in whole-mount sections from prostatectomy specimens by an experienced pathologist who was blinded to MRI. The region of interest used for radiomics analysis included the prostatic index tumor. Radiomics extraction yielded 165 features using a special evaluation version of RadiomiX [RadiomiX Research Toolbox version 20180831 (OncoRadiomics SA, Liège, Belgium)] for non-clinical use. Multivariable logistic regression with Elastic Net regularization was utilised using 10 times repeated 10-fold cross-validation to select the best model hyperparameters, optimizing for area under the receiver operating characteristic curve (AUC). RESULTS: The average (out of sample) performance based on the repeated cross validation using the ONESE model yielded an AUC of 0.60±0.2. Shape-based features were the most prominent in the model. CONCLUSION: The development of a radiomics hypoxia model using T2 weighted MR images, standard in the staging of prostate cancer, is possible.

First-in-human technique translation of oxygen-enhanced MRI to an MR Linac system in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Tumour hypoxia is prognostic in head and neck cancer (HNC), associated with poor loco-regional control, poor survival and treatment resistance. The advent of hybrid MRI - radiotherapy linear accelerator or 'MR Linac' systems - could permit imaging for treatment adaptation based on hypoxic status. We sought to develop oxygen-enhanced MRI (OE-MRI) in HNC and translate the technique onto an MR Linac system. MATERIALS AND METHODS: MRI sequences were developed in phantoms and 15 healthy participants. Next, 14 HNC patients (with 21 primary or local nodal tumours) were evaluated. Baseline tissue longitudinal relaxation time (T1) was measured alongside the change in 1/T1 (termed ΔR1) between air and oxygen gas breathing phases. We compared results from 1.5 T diagnostic MR and MR Linac systems. RESULTS: Baseline T1 had excellent repeatability in phantoms, healthy participants and patients on both systems. Cohort nasal concha oxygen-induced ΔR1 significantly increased (p < 0.0001) in healthy participants demonstrating OE-MRI feasibility. ΔR1 repeatability coefficients (RC) were 0.023-0.040 s-1 across both MR systems. The tumour ΔR1 RC was 0.013 s-1 and the within-subject coefficient of variation (wCV) was 25% on the diagnostic MR. Tumour ΔR1 RC was 0.020 s-1 and wCV was 33% on the MR Linac. ΔR1 magnitude and time-course trends were similar on both systems. CONCLUSION: We demonstrate first-in-human translation of volumetric, dynamic OE-MRI onto an MR Linac system, yielding repeatable hypoxia biomarkers. Data were equivalent on the diagnostic MR and MR Linac systems. OE-MRI has potential to guide future clinical trials of biology guided adaptive radiotherapy.

Subsurface interactions of Fe(II) with humic acid or landfill leachate do not control subsequent iron(III) (hydr)oxide production at the surface.

At least 93% of Fe(II) remained free, as defined by ferrozine assay under anoxic conditions in the presence of humic acid (HA) and two simulated landfill leachates of different maturities. However, tangential flow ultrafiltration showed a weaker but more extensive interaction of Fe with organic carbon (OC); 90% of Fe associated with the less mature leachate. Despite the existence of this weak interaction under anoxic conditions, there was no difference in iron(III) (hydr)oxide production whether HA was added prior to or coincident with the oxidation of Fe(II) on exposure to oxic conditions. Under oxic conditions ferrozine showed that more Fe(II) bound to OC, up to 50% to HA. However, this occurs via oxidation of Fe(II) to Fe(III), which is bound and then thermally reduced. This affinity for Fe(III) and the ability to carry out thermal reduction both increase with the maturity of the OC. The rate at which ferrozine-defined free Fe(II) was lost on exposure to dissolved oxygen was also enhanced by the more mature OC, while it was slowed by acetogenic leachate. The slowing must be a consequence of the filtration-defined Fe(II)/OC interaction.

Preventable childhood injuries.

BACKGROUND: This is a literature review generated from The Committee on Trauma and Prevention of Pediatric Orthopaedic Society of North America to bring to the forefront 4 main areas of preventable injuries in children. METHODS: Literature review of pertinent published studies or available information of 4 areas of childhood injury: trampoline and moonbouncers, skateboards, all-terrain vehicles, and lawn mowers. RESULTS: Much literature exists on these injuries. CONCLUSIONS: Preventable injuries occur at alarming rates in children. By arming the orthopaedist with a concise account of these injuries, patient education and child safety may be promoted. LEVEL OF EVIDENCE: 3.

Impact of fractures on school attendance.

BACKGROUND: The purpose of this study was to determine the average prevalence of children across the nation who experience difficulty in attending school after an acute orthopaedic injury. METHODS: A survey was created to obtain information on school absence for children with acute orthopaedic injuries. All members of the Pediatric Orthopaedic Society of North America were invited to complete the survey. RESULTS: The survey was sent by e-mail to 936 members of the Pediatric Orthopaedic Society of North America. A total of 283 surgeons from 45 states responded to the survey, which resulted in a response rate of 30.2%. The survey found a correlation with difficulty in attending school with a cast and the size of the population served. Communities with the larger populations are less likely to permit children to attend school with a cast. The most common reasons given by schools for a child not being permitted to attend school with a cast were concern for the safety of the child and inability to accommodate the needs of the child. CONCLUSIONS: Most physicians participating in the survey reported no difficulty with their patients attending school with a cast. There was more difficulty with children in attending school with a cast in metropolitan areas and in communities with greater than 1 million people. To decrease or to eliminate absence from school, it may be best to identify schools in a physician's community that do not allow attendance of children with a cast. Once individual schools are identified, advocacy can be targeted. At the very least, when it is known which schools are involved, the surgeon can anticipate difficulties and plan accordingly. As a child's absence from school has substantial negative consequences, we strongly support intervention to enable injured children to appropriately return to a regular educational setting in a timely manner. Future studies with school participation would help to identify reasons for school absence after a musculoskeletal injury. LEVEL OF EVIDENCE: Level V, Prognostic.

Prevalence of Hip Ultrasound Abnormalities in Newborns With a Hip Click.

A hip click on examination of the newborn hip is believed to be the result of a ligament or myofascial structure and thought to be benign. Some studies suggest a link between hip clicks and developmental dysplasia of the hip. The purpose of our study is to estimate the prevalence of ultrasound hip abnormalities in newborns with a hip click and an otherwise normal physical examination. Results. Ninety patients meeting inclusion criteria of a hip click with an otherwise normal physical examination underwent diagnostic ultrasound with a 17.8% prevalence of hip abnormalities found (95% confidence interval ±7.9% [range of 9.9% to 25.7%]). Our study had 64 (71%) females and 26 (29%) males. The prevalence of hip pathology for females was 18.8% (12 of 64 patients) and for males was 15.4% (4 of 26 patients). Thirty-three patients were found to have bilateral hip clicks on presentation, with 21.2% (7 of 33) of those patients found to have hip pathology on ultrasound (3 of the 7 had pathology of both hips). Six patients had a family history of hip dysplasia and 1 of these patients (16.7%) had pathology on ultrasound. The average age to hip sonography was 6.6 weeks. Conclusions. In all, 17.8% of newborns with a hip click were found to have hip abnormalities on ultrasound. The prevalence of hip pathology, on ultrasound, suggests that additional larger, prospective studies are needed to clarify the association between a hip click and abnormal ultrasound found at 6 weeks of age or greater.

Stilbene glycosides are natural product inhibitors of FGF-2-induced angiogenesis.

BACKGROUND: Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with pathological processes, in particular tumour development, and is a target for the development of new therapies. We have investigated the anti-angiogenic potential of two naturally occurring stilbene glycosides (compounds 1 and 2) isolated from the medicinal plant Boswellia papyriferai using large and smallvessel-derived endothelial cells. Compound 1 (trans-4',5'-dihydroxy-3-methoxystilbene-5-O-{alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->6)}-beta-D-glucopyranoside was the more hydrophilic and inhibited FGF-2-induced proliferation, wound healing, invasion in Matrigel, tube formation and angiogenesis in large and small vessel-derived endothelial cells and also in the chick chorioallantoic membrane assay. Using a binding assay we were able to show compound 1 reduced binding of FGF-2 to fibroblast growth factor receptors-1 and -2. In all cases the concentration of compound 1 which caused 50% inhibition (IC50) was determined. The effect of compound 1 on EGF and VEGF-induced proliferation was also investigated. RESULTS: Compound 1 inhibited all stages of FGF-2 induced angiogenesis with IC50 values in the range 5.8 +/- 0.18 - 48.90 +/- 0.40 microM but did not inhibit EGF or VEGF-induced angiogenesis. It also inhibited FGF-2 binding to FGF receptor-1 and -2 with IC50 values of 5.37 +/- 1.04 and 9.32 +/- 0.082 muM respectively and with concommotant down-regulation of phosphorylated-ERK-1/-2 expression. Compound 2 was an ineffective inhibitor of angiogenesis despite its structural homology to compound 1. CONCLUSION: Compound 1 inhibited FGF-2 induced angiogenesis by binding to its cognate receptors and is an addition to the small number of natural product inhibitors of angiogenesis.

Tibia fractures in children sustained on a playground slide.

BACKGROUND: The purpose of this study is to investigate the relationship between children who sustain tibia fractures on a playground slide and the mechanism of injury. METHODS: This retrospective review included the chart and radiographs of all children diagnosed with a tibia fracture, over an 11-month period. All patients were originally seen in either the emergency room of a level 1 trauma center or the treating physician's office. RESULTS: During the period of study, 58 fractures of the tibia were found. Eight (13.8%) of the tibia fractures were sustained while playing on a playground slide. The 8 fractures identified are the focus of this study. The tibia fractures were nondisplaced, diaphyseal, with an intact fibula. There were 5 female and 6 male children included in the study. The age range of the patients with a tibia fracture sustained while going down a slide was 14 months to 32 months; the average age of the 8 children in this study was 20.6 months. The average age of boys sustaining a tibia fracture on a playground slide was found to be 20.7 months and the average age of girls was found to be 20.6 months. All tibia fractures associated with playing on a slide were sustained while going down the slide on the lap of an adult. None of the 8 children studied went down the slide alone. CONCLUSIONS: Children at risk for tibia fractures sustained while going down a playground slide, on the lap of an adult, were found to be less than 32 months of age. Many parents believe they are increasing the safety of their young child by placing the child on their lap while going down a playground slide. Parents should be educated not to go down a slide with a child on their lap. If the child is unable to use the slide independently, another activity would be more appropriate. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Conversion of a Conference Room into a Low-Acuity Inpatient Medical Unit: A Creative Response to Influenza-Related Surge.

The 2017-2018 influenza season was associated with high demand for both emergency department (ED) care and inpatient acute care for influenza-like illness (ILI). This high demand resulted in increased numbers of inpatients and ED patients, including prolonged ED length of stay. A large, urban, academic medical center in a cold-weather region was limited in its ability to expand its footprint to create de novo locations of care, such as temporary outbuildings or tents. As such, a large conference room was rapidly converted and placed in service as a temporary inpatient unit for adults requiring inpatient admission. LOGISTICS AND IMPLEMENTATION: The logistical, infection prevention, safety, information technology, staffing, and other concerns of creating a clinical environment during a high demand scenario is challenging. However, the lessons learned in this study are reproducible despite the complexity of this issue. CONCLUSION: This is believed to be the first published account of successful conversion of a nonclinical area to an operational clinical unit in response to a surge in demand for hospital care and admission. This may be a valid option for hospitals of all sizes as part of a surge or disaster plan.

Cheiradone: a vascular endothelial cell growth factor receptor antagonist.

BACKGROUND: Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with physiological (for example wound healing) and pathological conditions (tumour development). Vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) and epidermal growth factor (EGF) are the major angiogenic regulators. We have identified a natural product (cheiradone) isolated from a Euphorbia species which inhibited in vivo and in vitro VEGF- stimulated angiogenesis but had no effect on FGF-2 or EGF activity. Two primary cultures, bovine aortic and human dermal endothelial cells were used in in vitro (proliferation, wound healing, invasion in Matrigel and tube formation) and in vivo (the chick chorioallantoic membrane) models of angiogenesis in the presence of growth factors and cheiradone. In all cases, the concentration of cheiradone which caused 50% inhibition (IC50) was determined. The effect of cheiradone on the binding of growth factors to their receptors was also investigated. RESULTS: Cheiradone inhibited all stages of VEGF-induced angiogenesis with IC50 values in the range 5.20-7.50 microM but did not inhibit FGF-2 or EGF-induced angiogenesis. It also inhibited VEGF binding to VEGF receptor-1 and 2 with IC50 values of 2.9 and 0.61 microM respectively. CONCLUSION: Cheiradone inhibited VEGF-induced angiogenesis by binding to VEGF receptors -1 and -2 and may be a useful investigative tool to study the specific contribution of VEGF to angiogenesis and may have therapeutic potential.

Dynamin and perforin are associated with neovascularisation in advanced carotid plaques.

Intimal plaque neovascularization is associated with the development of symptomatic disease and thrombosis, with new 'leaky' fragile microvessels prone to haemorrhage. Perforin or pore forming protein is involved in vascular cell death by forming pores in target cells. Enzymes, in particular, granzyme B are secreted by immune infiltrates present in inflammatory plaque regions and have been shown to induce endothelial cell apoptosis. Similarly, dynamin-2 is a GTPase which mediates oxidised low density lipoprotein-induced apoptosis and is also required for granzyme B-mediated exocytosis and apoptosis. Our pilot studies identified increased expression of these proteins in complicated atherosclerotic plaques. Here we demonstrate by immunohistochemistry that both proteins are over-expressed in angiogenic regions of complicated carotid plaques. Dynamin-2 was extensively localised around microvessels and in immune infiltrating cells whilst perforin was localised in immune infiltrating cells, endothelial cells and smooth muscle cells. Over-expression of these proteins may contribute to plaque destabilisation by increasing cellular apoptosis in vulnerable atherosclerotic plaques.

The normal cellular prion protein and its possible role in angiogenesis.

Cellular Prion Protein (PrPc) is a ubiquitous glycoprotein present on the surface of endothelial cells. Resting vascular endothelial cells show minimum expression of PrPc and can constitutively release PrPc. PrPc participates in cell survival, differentiation and angiogenesis. During development, neonatal brain endothelial cells transiently express PrPc. Our group recently reported upregulation of PrPc in microvessels from ischemic brain regions in stroke patients. Ischemia/hypoxia induces PrPc expression through the activation of extracellular signal-regulated kinase (ERK). All these data suggest that PrPc plays an important role in angiogenic responses. In addition, PrPc participates in cellular function in the central nervous system, since PrPc is also highly expressed in neurons. PrPc binds copper, suggesting a role in copper metabolism. PrPc also protects cells against oxidative stress and it seems to be involved in neuroprotection. Several studies have demonstrated that PrPc prevents cells from apoptosis and subsequent tissue damage. Moreover, PrPc plays an important role in the immune response. Here, we review the multiple functions of PrPc with a special attention to its recently reported role in angiogenesis.

Decreasing Unplanned Office Visits Due to Cast Problems in the Pediatric Population.

INTRODUCTION: Unplanned office visits due to cast-related problems in the pediatric orthopedic office are common. Decreasing problems associated with the use of a cast would improve patient safety, increase office productivity, and decrease inconvenience to the child and family. METHODS: Pediatric patients treated with a cast in our office were included in the study if they returned for an unplanned office visit due to a cast-related problem. Group 1 received verbal cast care instruction. Group 2 had the same verbal instruction in addition to a written handout identical to the verbal instructions. Group 3 was provided the same verbal instructions and a revised handout limiting the number of instructions and focused on keeping the cast away from water. RESULTS: The study included 550 patients with 146 in group 1, 124 in group 2, and 280 in group 3. Comparing group 1 (10.3%) and group 2 (10.5%), there was almost no difference in the rate of unplanned office visits due to cast-related problems. Combining the revised handout with verbal instructions in group 3, the percentage of patients returning for an unplanned visit was 6%. There was a relative decrease in office visits by 55% and an absolute decrease of 4.5% when comparing group 2 and group 3. CONCLUSIONS: There was a decrease in the number of unplanned office visits due to cast problems utilizing a handout focused on keeping the cast dry in collaboration with verbal cast care instructions. However, the decrease was not statistically significant.

Comparison of protective effects of aspirin, D-penicillamine and vitamin E against high glucose-mediated toxicity in cultured endothelial cells.

This study compared the protective effects of three different anti-glycation compounds, aspirin, D-penicillamine and vitamin E, against high glucose and advanced glycation endproduct (AGE) mediated toxicity in cultured bovine aortic endothelial cells using two approaches. Their proliferation was assessed in culture in different concentrations of glucose (5.5-100 mmol/l) with and without these inhibitors. A monolayer of cultured endothelial cells was wounded and recovery at the wound site was measured following exposure to different concentrations of glucose with and without inhibitors. The ability of these compounds to protect cultured endothelial cells following exposure to bovine serum albumin-derived advanced glycation endproducts (BSA-AGE) was also studied. Addition of glucose to cultured endothelial cells inhibited their proliferation in a dose dependent manner. All three compounds protected against the anti-proliferative effects of high glucose, with vitamin E being the most effective. The migration of cultured endothelial cells following wounding was inhibited by increasing concentrations of glucose but was maintained in the presence of all three anti-glycation compounds with vitamin E, again giving the greatest protection. Vitamin E was also the most effective at protecting against the anti-proliferative effects of BSA-AGE. D-penicillamine was not as effective as vitamin E whereas aspirin offered no significant protection against AGE-induced cellular toxicity. Our studies suggest that compounds, such as vitamin E, with combined antiglycation and antioxidant properties offer maximum therapeutic potential in protection against high glucose and AGE-mediated cellular toxicity.

Expression of cyclin-dependent kinase 5 mRNA and protein in the human brain following acute ischemic stroke.

Neuronal cell death after brain ischemia may be regulated by activation of cyclin-dependent kinase 5 (Cdk5). In this study, expression of Cdk5 and its activator p35/p25 was examined in human post-mortem stroke tissue and in human cerebral cortical fetal neurons and human brain microvascular endothelial cells exposed to oxygen-glucose deficiency and reperfusion. The majority of patients demonstrated increased expression of Cdk5 and p-Cdk5 in stroke-affected tissue, with about a third showing increased p35 and p25 cleaved fragment as determined by Western blotting. An increase in Cdk5-, p-Cdk5- and p35-positive neurons and microvessels occurred in stroke-affected regions of patients. Staining of neurons became irregular and clumped in the cytoplasm, and nuclear translocation occurred, with colocalization of p35 and Cdk5. Association of Cdk5 with nuclear damage was demonstrated by coexpression of nuclear Cdk5 in TUNEL-positive neurons and microvessels in peri-infarcted regions. In vitro studies showed up-regulation and/or nuclear translocation of Cdk5, p-Cdk5 and p35 in neurons and endothelial cells subjected to oxygen-glucose deficiency, and strong staining was associated with propidium iodide positive nuclei, an indicator of cellular damage. These results provide new evidence for a role of Cdk5 in the events associated with response to ischemic injury in humans.

Hyaluronan-mediated angiogenesis in vascular disease: uncovering RHAMM and CD44 receptor signaling pathways.

The correct formation of new blood vessels from existing vasculature (angiogenesis) is essential for embryogenesis and the effective repair of damaged or wounded tissues. However, excessive and detrimental vascularization also occurs in neoplasia, promoting tumour growth and metastasis, as well as in proliferative diabetic retinopathy and atherosclerosis. Greater understanding of the mechanisms controlling the angiogenic process will allow optimization of wound healing, and provide mechanisms to inhibit vascularization in tumours and other diseases. Evidence supports a cascade of events in which the perturbation of one of the steps is sufficient to significantly inhibit neovascularization. The extracellular macromolecules, notably glycosaminoglycans (GAGs), are important mediators of angiogenesis. Hyaluronan (HA), a large, non-sulphated GAG, was first discovered in the vitreous of the eye [.], and is ubiquitously expressed in the extracellular matrix (ECM) of tissues. Native high molecular weight HA (n-HA) is anti-angiogenic, whereas HA degradation products (o-HA; 3-10 disaccharides) stimulate endothelial cell (EC) proliferation, migration and tube formation following activation of specific HA receptors in particular, CD44 and Receptor for HA-Mediated Motility (RHAMM, CD168). The involvement of HA in the regulation of angiogenesis makes it an attractive therapeutic target. We review the role of o-HA in modulation of angiogenesis during tissue injury, and vascular disease, focusing on receptor-mediated signal transduction pathways that have been evaluated.

A microarray study of gene and protein regulation in human and rat brain following middle cerebral artery occlusion.

BACKGROUND: Altered gene expression is an important feature of ischemic cerebral injury and affects proteins of many functional classes. We have used microarrays to investigate the changes in gene expression at various times after middle cerebral artery occlusion in human and rat brain. RESULTS: Our results demonstrated a significant difference in the number of genes affected and the time-course of expression between the two cases. The total number of deregulated genes in the rat was 335 versus 126 in the human, while, of 393 overlapping genes between the two array sets, 184 were changed only in the rat and 36 in the human with a total of 41 genes deregulated in both cases. Interestingly, the mean fold changes were much higher in the human. The expression of novel genes, including p21-activated kinase 1 (PAK1), matrix metalloproteinase 11 (MMP11) and integrase interactor 1, was further analyzed by RT-PCR, Western blotting and immunohistochemistry. Strong neuronal staining was seen for PAK1 and MMP11. CONCLUSION: Our findings confirmed previous studies reporting that gene expression screening can detect known and unknown transcriptional features of stroke and highlight the importance of research using human brain tissue in the search for novel therapeutic agents.