Severe amygdala dysfunction in a MAPT transgenic mouse model of frontotemporal dementia

Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is a neurodegenerative tauopathy caused by mutations in the tau gene (MAPT). Individuals with FTDP-17 have deficits in learning, memory, and language, in addition to personality and behavioral changes that are often characterized by a lack of social inhibition. Several transgenic mouse models expressing tau mutations have been tested extensively for memory or motor impairments, though reports of amygdala-dependent behaviors are lacking. To this end, we tested the rTg4510 mouse model on a behavioral battery that included amygdala-dependent tasks of exploration. As expected, rTg4510 mice exhibit profound impairments in hippocampal-dependent learning and memory tests, including contextual fear conditioning. However, rTg4510 mice also display an abnormal hyperexploratory phenotype in the open-field assay, elevated plus maze, light-dark exploration, and cued fear conditioning, indicative of amygdala dysfunction. Furthermore, significant tau burden is detected in the amygdala of both rTg4510 mice and human FTDP-17 patients, suggesting that the rTg4510 mouse model recapitulates the behavioral disturbances and neurodegeneration of the amygdala characteristic of FTDP-17.     

Appendicular myological reconstruction of the forelimb of the giant titanosaurian sauropod dinosaur Dreadnoughtus schrani

Soft tissues are variably preserved in the fossil record with external tissues, such as skin and feathers, more frequently preserved than internal tissues (e.g. muscles). More commonly, soft tissues leave traces of their locations on bones and, for muscles, these clues can be used to reconstruct the musculature of extinct vertebrates, thereby enhancing our understanding of how these organisms moved and the evolution of their locomotor patterns. Herein we reconstruct the forelimb and shoulder girdle musculature of the giant titanosaurian sauropod Dreadnoughtus schrani based on observations of osteological correlates and dissections of taxa comprising the Extant Phylogenetic Bracket of non-avian dinosaurs (crocodilians and birds). Fossils of Dreadnoughtus exhibit remarkably well-preserved, well-developed, and extensive muscle scars. Furthermore, this taxon is significantly larger-bodied than any titanosaurian for which a myological reconstruction has previously been attempted, rendering this myological study highly informative for the clade. In total, 28 muscles were investigated in this study, for which 46 osteological correlates were identified; these osteological correlates allowed the reconstruction of 16 muscles on the basis of Level I or Level II inferences (i.e. not Level I' or Level II' inferences). Comparisons with other titanosaurians suggest widespread myological variation in the clade, although potential phylogenetic patterns are often obscured by fragmentary preservation, infrequent myological studies, and lack of consensus on the systematic position of many taxa. By identifying myological variations within the clade, we can begin to address specific evolutionary and biomechanical questions related to the locomotor evolution in these sauropods.     

Intravenously administered nanoparticles increase survival following blast trauma

Explosions account for 79% of combat-related injuries, leading to multiorgan hemorrhage and uncontrolled bleeding. Uncontrolled bleeding is the leading cause of death in battlefield traumas as well as in civilian life. We need to stop the bleeding quickly to save lives, but, shockingly, there are no treatments to stop internal bleeding. A therapy that halts bleeding in a site-specific manner and is safe, stable at room temperature, and easily administered is critical for the advancement of trauma care. To address this need, we have developed hemostatic nanoparticles that are administered intravenously. When tested in a model of blast trauma with multiorgan hemorrhaging, i.v. administration of the hemostatic nanoparticles led to a significant improvement in survival over the short term (1 h postblast). No complications from this treatment were apparent out to 3 wk. This work demonstrates that these particles have the potential to save lives and fundamentally change trauma care.On the battlefield, hemorrhage is a leading cause of preventable death (1). Blast injuries account for 79% of combat-related injuries and the majority of cases of traumatic brain injury (2). There are three classifications of blast injury: primary, secondary, and tertiary. Primary blast injuries refer to the direct effects of the overpressure wave, whereas secondary and tertiary insults result from objects propelled by the blast wind and the individual being thrown against other objects, respectively. Owing to the rapid change in pressure, blast traumas can involve hemorrhage in multiple organs, particularly the air-filled organs, brain, and spinal cord.Blast trauma is unique and difficult to treat because it can damage multiple organs and cause significant hemorrhaging. The shocking reality is that there are no treatments for internal bleeding, although early intervention is essential to minimizing the mortality associated with severe trauma (3). Uncontrolled bleeding is no less lethal beyond the battlefield, being the leading cause of death for civilians age 5–44 y (4, 5).We need a therapy that can be administered in the field to stop internal bleeding. This therapy must be extremely safe, stable at room temperature, and easily administered. Various therapies, ranging from platelets to recombinant factors to microparticles and nanoparticles, have been considered to date. Administration of allogeneic platelets confers a significant survival advantage in patients with massive trauma, but these platelets have a short shelf life, and administration can cause graft-versus-host disease, alloimmunization, and transfusion-associated lung injuries (6–8). These problems motivated the development of platelet substitutes. Typically, these nanoparticles and microparticles take advantage of the clotting cascade through peptide binding to receptors on activated platelets such as the glycoprotein IIb/IIIa receptor, which can bind fibrinogen, Arg-Gly-Asp (RGD), and dodecapeptide-H12 (HHLGGAKQAGDV). Early designs included RGD-conjugated red blood cells, which were effective in vitro and fibrinogen-coated albumin microparticles, which significantly reduced bleeding time and volume in thrombocytopenic rabbits (9, 10). Platelet-derived particles showed promising results in vitro and in thrombocytopenic rabbits, but did not significantly reduce prolonged bleeding times in thrombocytopenic primates (11, 12). Liposomal nanoparticles are also a potential synthetic core for particles, and particles decorated with RGD and the von Willebrand factor-binding peptide VBP promoted platelet aggregation in vivo and reduced bleeding time in a mouse tail bleeding model (13). Similarly, liposomes carrying the fibrinogen γ chain dodecapeptide (HHLGGAKQAGDV) (14, 15) were effective in thrombocytopenic rats, but might not be effective in healthy models.In addition to the platelet mimics, recombinant factor 7 (rFVIIa; NovoSeven) has been used to augment hemostasis by supplementing the coagulation cascade. Although rFVIIa can control or reduce massive bleeding in trauma patients, immunogenic and thromboembolic complications are unavoidable risks (16, 17). Nevertheless, rFVIIa is used in the clinic in trauma and surgical situations when bleeding cannot be controlled through other means (16). The data on rFVIIa’s efficacy is variable, and it is very expensive; a single dose costs approximately $10,000, and multiple doses are typically needed to impact hemostasis (16). We need an effective, safe therapy for the field.To address this need, we have developed hemostatic nanoparticles that can halt bleeding when delivered intravenously (18–20). We hypothesized that administration of these hemostatic nanoparticles could increase short-term and long-term survival following blast trauma. We developed a full-body blast model that replicates the injuries seen in personnel exposed to explosions, and tested the effects of administration of hemostatic nanoparticles, control nanoparticles, saline, and rFVIIa on survival, hemorrhaging, and behavioral outcomes following blast trauma.     

Regulation of polyurethane hemocompatibility and endothelialization by tethered hyaluronic acid oligosaccharides

Current synthetic vascular grafts possess a significant mechanical mismatch compared to the native vasculature and do not permit endothelialization; both of these deficiencies contribute to the relatively high rate of failure of many synthetic grafts. In this communication, we report the modification of polyurethane (PU)-based materials to impart hemocompatibility, support endothelial growth, and display vascular-appropriate mechanics. This modification was achieved by incorporating branched polyethylenimine (PEI) into the PU backbone, followed by covalent attachment of either hyaluronic acid (HA; 4.7, 64, and 104 kDa), heparin, or poly(ethylene glycol) (PEG; used as a non-adhesive control) to the PEI. This grafting chemistry resulted in comparatively dense immobilization of HA and heparin (0.062 and 2.3 μg/cm², respectively) to the PU–PEI surfaces. PU materials modified with HA were more effective than either PEG- or heparin-grafted materials with respect to limiting protein adsorption and platelet adhesion. Confluent, morphologically-healthy cultures of endothelial cells were achieved only on materials grafted with low molecular weight HA, but not high MW HA, heparin, or PEG. These modifications in PU chemistry were performed while retaining material mechanics in the range of native vascular tissue. Thus, this study describes the generation of materials that possess the unique ability to display excellent hemocompatibility while simultaneously supporting extensive endothelialization and retaining vascular-appropriate mechanics. The bioactivity of these materials was regulated by the molecular weight of the grafted HA, and their physical and biological properties make them promising for use as vascular grafts.     

Colorectal cancer and its prevention: prevalence of beliefs,attitudes, intentions and behaviour

Abstract: There is so far only limited evidence from randomised controlled trials that screening for colorectal cancer using the faecal occult blood test produces significant mortality reductions in screened groups, but there is considerable activity and interest in the use of such screening in Australia. Beliefs, attitudes, intentions and behaviour in relation to colorectal cancer and screening were examined among participants 40 years and older (n = 1776) who took part in a representative population survey. While there were high levels of awareness of faecal occult blood test screening, most respondents had not had a test, nor did they intend to take a test in the future. Important determinants of participation in screening were a family history of colorectal cancer, a belief that bowel cancer can be cured if detected at an early stage, a perception of personal susceptibility to bowel cancer and an acceptance of the technique. Factors such as these are likely to influence the success of any future screening program in Australia.     

Smaller aortic dimensions do not fully account for the greater pulse pressure in elderly female hypertensives

This study examined the importance of aortic dimensions in determining pulse pressure in elderly hypertensives participating in the 2nd Australian National Blood Pressure Study, including a substantial number not previously receiving blood pressure lowering medication. Aortic dimensions were determined by ultrasound at the transverse arch and at the insertion of the aortic valve. Unadjusted data showed negative (P<0.001) correlations between central (carotid) and (brachial) peripheral pulse pressure and both arch (-0.200, -0.181) and outflow tract (-0.238, -0.238) diameters. Correlations were similar in those previously treated with blood pressure lowering medication and in the treatment na?ve. Central pulse pressure (84+/-26 versus 75+/-28 mm Hg, P<0.001) was higher and aortic dimensions (transverse arch 2.56+/-0.31 versus 2.88+/-0.35 mm, P<0.001) smaller in women than men. Women had greater aortic stiffness (beta index 29.4+/-36.1 versus 22.1+/-21.3, P<0.03). Other bivariate correlates of central pulse pressure were age, mean arterial pressure, height, heart rate, augmentation index, aortic stiffness (all P<0.001), and weight (P=0.027). In multivariate analyses gender remained a predictor of central pulse pressure (P<0.001) even with inclusion of aortic dimensions (P=0.013) height and weight. Other significant terms were age, heart rate, mean blood pressure, and aortic stiffness (all P<0.001). These findings demonstrate an independent inverse relation between aortic size and pulse pressure in older hypertensive subjects. Differences in aortic dimensions and stiffness between genders do not fully account for the observed blood pressure differences, suggesting that a contributory factor to gender differences in pulse pressure is an increased age-related mismatch in ventricular function and aortic stiffness in women compared with men.     

Quality of anticoagulation care in patients discharged from a pharmacist-managed anticoagulation clinic after stabilization of warfarin therapy

STUDY OBJECTIVE: To determine if transitioning patients from a pharmacist- managed anticoagulation clinic after stabilization of warfarin therapy to physician-managed care alters the quality of anticoagulation care. DESIGN: Retrospective medical record review. SETTING: Pharmacist-managed, urban academic medical center-based outpatient anticoagulation clinic. PATIENTS: Forty patients who were stabilized on warfarin therapy. MEASUREMENTS AND MAIN RESULTS: Quality of anticoagulation care was measured by percentage of international normalized ratios (INRs) in target range, anticoagulation-related health care visits, and responses to satisfaction surveys. A significant decrease in anticoagulation control was observed on transition to physician-managed care. Before transition, 76% of all INRs were in target range versus 48% after transition (p<0.0001, chi(2) test). When performing paired analysis, a median 75% of each patient's INRs were therapeutic before transition compared with 36.5% after (p<0.0001, Wilcoxon signed rank test). Thirty-two percent of first INR values measured after transition from the clinic were in target range, and the median time to first follow-up INR was 41 days. The number of INR values above 4.5 and below 1.5 increased significantly after transition from the anticoagulation clinic (p<0.0001 and p=0.01, respectively, chi(2) test). Before transition from the anticoagulation clinic, two anticoagulation-related emergency department visits were reported in one patient. After transition, 13 cases of additional medical care were reported among seven patients; seven of the 13 cases required an office visit with the physician, and six resulted in emergency room evaluation. None of these cases resulted in hospitalization. Patient satisfaction with clinical care provided by the anticoagulation clinic was significantly higher before transition. CONCLUSION: Transition of patients from a pharmacist-managed anticoagulation clinic back to physician-managed anticoagulation care after stabilization of warfarin therapy was associated with a significant decrease in INR control, increased medical care related to anticoagulation, and decreased patient satisfaction.     

Oxidative stress in a rat model of chronic gliosis

Alzheimer's disease is a progressive neurodegenerative disorder characterised by abnormal extracellular deposition of a 4 kDa peptide termed beta-amyloid, neuronal loss, oxidative stress and chronic astrocytosis and microgliosis, but how the latter two features contribute to the progression of the disease is poorly understood. We have previously demonstrated in a novel in vivo transplantation model that chronic astro- and microgliosis resulted in molecular pathology similar to that observed in the Alzheimer's disease brain. We now report that these heterotopic, gliotic transplants exhibit prolonged oxidative stress, characterised by lipid peroxidation and protein carbonyl formation. Furthermore, we demonstrate that dietary additives can elevate endogenous anti-oxidant defences and reduce oxidative stress without attenuating astro- and microgliosis. We also show that administration of ibuprofen through the drinking water results in a similar reduction in oxidative stress but with no observable effect on glial reactivity. The present study lends support to the notion that dietary anti-oxidants and non-steroidal anti-inflammatory drugs may be potential preventative agents against some of the pathological processes associated with neurodegenerative disease.     

In-shoe plantar pressure measurements for patients with knee osteoarthritis: Reliability and effects of lateral heel wedges

Although plantar pressure measurement systems are being used increasingly during gait analyses to investigate foot orthotics, there is limited information describing test–retest reliability of such measurements. Objectives of this study were to (1) examine the test–retest reliability of lateral heel pressure (LHP) and centre of pressure (COP) during walking with and without lateral heel wedges, and (2) evaluate the effects of 4° and 8° lateral heel wedges on the magnitude of LHP, the pathway of the COP and the peak external knee adduction moment (KAM) in subjects with and without knee osteoarthritis (OA). Twenty-six subjects, 12 patients with knee OA and 14 healthy subjects, were evaluated during three lateral heel wedge conditions (control, 4° and 8°) with standardized footwear. Three-dimensional analyses of gait with optical motion capture, floor-mounted force plate and in-shoe plantar pressure were completed on two occasions. Intraclass correlation coefficients (ICC_{2, 1}) for LHP were excellent (0.79–0.83) while ICCs for COP in the medial–lateral and anterior–posterior directions were more variable (0.66–0.86). Reliability was slightly diminished when using heel wedges. Standard errors of measurement suggested considerable day-to-day variability in an individual's measures. Lateral heel wedges significantly (p < 0.001) increased LHP, shifted COP anteriorly and laterally, and decreased the KAM. No significant differences were observed between subjects with and without OA. Although the day-to-day variability appears too large to confidently evaluate changes in individual patients, and decreases in reliability with increases in wedge size indicate caution, these results suggest in-shoe measurement of LHP and COP are appropriate for use in studies evaluating biomechanical effects of foot orthoses for knee OA.