The role of the osteoclast during endochondral ossification in a rat fracture model

University of Technology Sydney. Faculty of Science.Bisphosphonates (BPs) are the most common treatment for osteoporosis, due to their powerful ability to inhibit osteoclastic bone resorption. They are also being investigated to augment callus production during fracture healing, however, concerns exist as to the effects of BPs during both initial fracture union and hard callus remodelling. Endochondral ossification during fracture repair is a critical process leading to initial union, and is assumed to be dependent on osteoclast function. Hard The role of osteoclasts during initial endochondral fracture union was investigated using the BP zoledronic acid (ZA) and in a genetic model of osteoclast inactivity, the incisor absent (ia/ia) rat. In addition, the effect of differing ZA treatment regimes on hard callus remodelling was investigated using both Bolus and Weekly ZA dosing. A Bolus of 0.1mg/kg ZA or 5 Weekly doses of 0.02mg/kg ZA or Saline were administered commencing 1 week post surgery in a rat femoral fracture model. Femoral fractures were also produced in ia/ia rats. Examinations were performed up to initial union and throughout callus remodelling. ZA treatment did not alter the rate of endochondral fracture union. All fractures united by 6 weeks, with no difference in the percentage of cartilaginous callus between treatment groups at any time point. Fracture union was achieved by 3 weeks in both ia/ia and control rats, again with no difference in the percentage of cartilaginous callus. In contrast, marked differences in hard callus were evident in the ZA treated groups. ZA increased callus bone mineral content, volume and importantly increased callus strength. Bolus ZA treatment did not delay the commencement of hard callus remodelling at 4 weeks post fracture, whereas this was delayed in the Weekly ZA group. By 12 and 26 weeks Bolus ZA had the same callus content of remodelled neo-cortical bone as Saline, however Weekly ZA had significantly less than saline at these times. These extensive delays in hard callus remodelling with Weekly ZA dosing produced a fracture callus of inferior material properties. In conclusion, neither ZA treatment nor the absence of active osteoclasts in ia/ia rats delayed endochondral fracture union. Thus, this study confirms the redundancy of osteoclasts in this process. Bolus ZA treatment was superior to Weekly ZA dosing; hard callus remodelling proceeded, producing a strong fracture callus with improved material properties. This study supports the use of less frequent ZA doses during fracture repair.callus remodelling, known to be dependent on osteoclast function, is important to the completion of bone repair

Size of hippocampal pyramidal neurons in schizophrenia

Background Meta-analyses of hippocampal size have indicated thatthis structure is smaller in schizophrenia.This could reflect a reductioninthe size of constituent neurons or a reduced number of neurons. Aims To measure the size of hippocampalpyramidalneuronsinthe hippocampalpyramidalneurons inthe brains of peoplewith andwithout schizophrenia. Method Pyramidalneuron size in hippocampal subfieldswas estimated stereologically fromsections taken at 5mmintervals throughoutthewhole length of right and left hippocampi from andleft the brains of13 peoplewith schizophrenia and16 controls.Resultswere assessed using repeated-measures analysis of covariance looking for amain effectof diagnosis and gender, andinteractions of and interactions thesewith side. Results Wewere unable to detect significantdifferences related to diagnosis, gender or side for any hippocampal subfield for this series of cases. Conclusions For this series of brains, hippocampal cell size is unchangedin schizophrenia

DNA Vaccines Encoding Antigen Targeted to MHC Class II Induce Influenza-Specific CD8+ T Cell Responses, Enabling Faster Resolution of Influenza Disease

Current influenza vaccines are effective but imperfect, failing to cover against emerging strains of virus and requiring seasonal administration to protect against new strains. A key step to improving influenza vaccines is to improve our understanding of vaccine induced protection. Whilst it is clear that antibodies play a protective role, vaccine induced CD8+ T cells can improve protection. To further explore the role of CD8+ T cells we used a DNA vaccine that encodes antigen dimerised to an immune cell targeting module. Immunising CB6F1 mice with the DNA vaccine in a heterologous prime boost regime with the seasonal protein vaccine improved the resolution of influenza disease compared to protein alone. This improved disease resolution was dependent on CD8+ T cells. However, DNA vaccine regimes that induced CD8+ T cells alone were not protective and did not boost the protection provided by protein. The MHC targeting module used was an anti-I-Ed single chain antibody specific to the BALB/c strain of mice. To test the role of MHC targeting we compared the response between BALB/c, C57BL/6 mice and an F1 cross of the two strains (CB6F1). BALB/c mice were protected, C57BL/6 were not and the F1 had an intermediate phenotype; showing that the targeting of antigen is important in the response. Based on these findings, and in agreement with other studies using different vaccines, we conclude that in addition to antibody, inducing a protective CD8 response is important in future influenza vaccines

Computerized ICU Data Management Pitfalls and Promises

journal articleBiomedical Informatic

Biodegradation of the Alkaline Cellulose Degradation Products Generated during Radioactive Waste Disposal.

The anoxic, alkaline hydrolysis of cellulosic materials generates a range of cellulose degradation products (CDP) including α and β forms of isosaccharinic acid (ISA) and is expected to occur in radioactive waste disposal sites receiving intermediate level radioactive wastes. The generation of ISA's is of particular relevance to the disposal of these wastes since they are able to form complexes with radioelements such as Pu enhancing their migration. This study demonstrates that microbial communities present in near-surface anoxic sediments are able to degrade CDP including both forms of ISA via iron reduction, sulphate reduction and methanogenesis, without any prior exposure to these substrates. No significant difference (n = 6, p = 0.118) in α and β ISA degradation rates were seen under either iron reducing, sulphate reducing or methanogenic conditions, giving an overall mean degradation rate of 4.7×10−2 hr−1 (SE±2.9×10−3). These results suggest that a radioactive waste disposal site is likely to be colonised by organisms able to degrade CDP and associated ISA's during the construction and operational phase of the facility

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the zinc-finger ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (p < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebelleum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737

Toeplitz operators with radial symbols on weighted holomorphic Orlicz space

Peer reviewe

Optimization of diagnostic imaging use in patients with acute abdominal pain (OPTIMA): Design and rationale

<p>Abstract</p> <p>Background</p> <p>The acute abdomen is a frequent entity at the Emergency Department (ED), which usually needs rapid and accurate diagnostic work-up. Diagnostic work-up with imaging can consist of plain X-ray, ultrasonography (US), computed tomography (CT) and even diagnostic laparoscopy. However, no evidence-based guidelines exist in current literature. The actual diagnostic work-up of a patient with acute abdominal pain presenting to the ED varies greatly between hospitals and physicians. The OPTIMA study was designed to provide the evidence base for constructing an optimal diagnostic imaging guideline for patients with acute abdominal pain at the ED.</p> <p>Methods/design</p> <p>Thousand consecutive patients with abdominal pain > 2 hours and < 5 days will be enrolled in this multicentre trial. After clinical history, physical and laboratory examination all patients will undergo a diagnostic imaging protocol, consisting of plain X-ray (upright chest and supine abdomen), US and CT. The reference standard will be a post hoc assignment of the final diagnosis by an expert panel. The focus of the analysis will be on the added value of the imaging modalities over history and clinical examination, relative to the incremental costs.</p> <p>Discussion</p> <p>This study aims to provide the evidence base for the development of a diagnostic algorithm that can act as a guideline for ED physicians to evaluate patients with acute abdominal pain.</p

Recent developments in Behavioural Public Policy: IBPPC 2022

Editorial

Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile

&lt;p&gt;Background: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.&lt;/p&gt; &lt;p&gt;Methods: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3).&lt;/p&gt; &lt;p&gt;Results: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies.&lt;/p&gt; &lt;p&gt;Conclusions: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.&lt;/p&gt