Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model

Background The bisphosphonate, zoledronic acid (ZOL), can inhibit osteoclasts leading to decreased osteoclastogenesis and osteoclast activity in bone. Here, we used a mixed osteolytic/osteoblastic murine model of bone-metastatic prostate cancer, RM1(BM), to determine how inhibiting osteolysis with ZOL affects the ability of these cells to establish metastases in bone, the integrity of the tumour-bearing bones and the survival of the tumour-bearing mice. Methods The model involves intracardiac injection for arterial dissemination of the RM1(BM) cells in C57BL/6 mice. ZOL treatment was given via subcutaneous injections on days 0, 4, 8 and 12, at 20 and 100 µg/kg doses. Bone integrity was assessed by micro-computed tomography and histology with comparison to untreated mice. The osteoclast and osteoblast activity was determined by measuring serum tartrate-resistant acid phosphatase 5b (TRAP 5b) and osteocalcin, respectively. Mice were euthanased according to predetermined criteria and survival was assessed using Kaplan Meier plots. Findings Micro-CT and histological analysis showed that treatment of mice with ZOL from the day of intracardiac injection of RM1(BM) cells inhibited tumour-induced bone lysis, maintained bone volume and reduced the calcification of tumour-induced endochondral osteoid material. ZOL treatment also led to a decreased serum osteocalcin and TRAP 5b levels. Additionally, treated mice showed increased survival compared to vehicle treated controls. However, ZOL treatment did not inhibit the cells ability to metastasise to bone as the number of bone-metastases was similar in both treated and untreated mice. Conclusions ZOL treatment provided significant benefits for maintaining the integrity of tumour-bearing bones and increased the survival of tumour bearing mice, though it did not prevent establishment of bone-metastases in this model. From the mechanistic view, these observations confirm that tumour-induced bone lysis is not a requirement for establishment of these bone tumours.

Persistence of multiple genetic lineages within intra-host populations of Ross River virus

We examined the structure and extent of genetic diversity in intrahost populations of Ross River virus (RRV) in samples from six human patients, focusing on the nonstructural (nsP3) and structural (E2) protein genes. Strikingly, although the samples were collected from contrasting ecological settings 3,000 kilometers apart in Australia, we observed multiple viral lineages in four of the six individuals, which is indicative of widespread mixed infections. In addition, a comparison with previously published RRV sequences revealed that these distinct lineages have been in circulation for at least 5 years, and we were able to document their long-term persistence over extensive geographical distances

Corneal nerve structure and function as markers of diabetic neuropathy

Diabetic neuropathy is a significant clinical problem that currently has no effective therapy, and in advanced cases, leads to foot ulceration and lower limb amputation. The accurate detection, characterisation and quantification of this condition are important in order to define at-risk patients, anticipate deterioration, monitor progression and assess new therapies. This thesis evaluates novel corneal methods of assessing diabetic neuropathy. Over the past several years two new non-invasive corneal markers have emerged, and in cross-sectional studies have demonstrated their ability to stratify the severity of this disease. Corneal confocal microscopy (CCM) allows quantification of corneal nerve parameters and non-contact corneal aesthesiometry (NCCA), the presumed functional correlate of corneal structure, assesses the sensitivity of the cornea. Both these techniques are quick to perform, produce little or no discomfort for the patient, and with automatic analysis paradigms developed, are suitable for clinical settings. Each has advantages and disadvantages over established techniques for assessing diabetic neuropathy. New information is presented regarding measurement bias of CCM images, and a unique sampling paradigm and associated accuracy determination method of combinations is described. A novel high-speed corneal nerve mapping procedure has been developed and application of this procedure in individuals with neuropathy has revealed regions of sub-basal nerve plexus that dictate further evaluation, as they appear to show earlier signs of damage than the central region of the cornea that has to date been examined. The discriminative capacity of corneal sensitivity measured by NCCA is revealed to have reasonable potential as a marker of diabetic neuropathy. Application of these new corneal markers for longitudinal evaluation of diabetic neuropathy has the potential to reduce dependence on more invasive, costly, and time-consuming assessments, such as skin biopsy.

Ownership structure and concentration and the timeliness of corporate earnings : Malaysian evidence

This thesis provides the first evidence on how ownership concentration and structure relate to the timeliness of price discovery and reporting lags in Malaysia. Based on a sample of 1,276 Malaysian firms from 1996 to 2009, the results show that ownership concentration and the identity of the largest shareholder matter to the timeliness of price discovery and reporting lags. Specifically, closely-held firms are more timely in their price discovery and have shorter reporting lags, particularly if the largest shareholder is a foreigner or a financial institution. Government-owned firms have longer reporting lags, as expected, but we find no evidence that family-owned firms have significantly different timeliness of price discovery and reporting lags than other firms. Additional analysis shows that prior to the implementation of the Malaysian Code of Corporate Governance, firms were more timely in their price discovery but longer in their reporting lag.

Characteristics of foot structure and footwear associated with hallux valgus : a systematic review

Objective Factors associated with the development of hallux valgus (HV) are multifactorial and remain unclear. The objective of this systematic review and meta-analysis was to investigate characteristics of foot structure and footwear associated with HV. Design Electronic databases (Medline, Embase, and CINAHL) were searched to December 2010. Cross-sectional studies with a valid definition of HV and a non-HV comparison group were included. Two independent investigators quality rated all included papers. Effect sizes and 95% confidence intervals (CIs) were calculated (standardized mean differences (SMDs) for continuous data and risk ratios (RRs) for dichotomous data). Where studies were homogeneous, pooling of SMDs was conducted using random effects models. Results A total of 37 papers (34 unique studies) were quality rated. After exclusion of studies without reported measurement reliability for associated factors, data were extracted and analysed from 16 studies reporting results for 45 different factors. Significant factors included: greater first intermetatarsal angle (pooled SMD = 1.5, CI: 0.88–2.1), longer first metatarsal (pooled SMD = 1.0, CI: 0.48–1.6), round first metatarsal head (RR: 3.1–5.4), and lateral sesamoid displacement (RR: 5.1–5.5). Results for clinical factors (e.g., first ray mobility, pes planus, footwear) were less conclusive regarding their association with HV. Conclusions Although conclusions regarding causality cannot be made from cross-sectional studies, this systematic review highlights important factors to monitor in HV assessment and management. Further studies with rigorous methodology are warranted to investigate clinical factors associated with HV.

The surface-structure sensitivity of dioxygen activation in the anatase-photocatalyzed oxidation reaction

The reaction pathways by which oxygen is incorporated into the substrate in the photocatalytic oxidation of terephthalic acid (TPTA) are vastly different on {001} and {101} facets of an anatase single crystal. This was established by controlling the percentage of {101} and {001} facets, isotopically tracing the origins of the hydroxy group, and studying dioxygen consumption and variance in the concentration of hydroxylation intermediate.

Orthopedic bone plates : evolution in structure implementation technique and biomaterial

With many important developments over the last century, nowadays orthopedic bone plate now excels over other types of internal fixators in bone fracture fixation. The developments involve the design, material and implementation techniques of the plates. This paper aims to review the evolution in implementation technique and biomaterial of the orthopedic bone plates. Plates were initially used to fix the underlying bones firmly. Accordingly, Compression plate (CP), Dynamic compression plate (DCP), Limited contact dynamic compression plate (LC-DCP) and Point contact fixator (PC-Fix) were developed. Later, the implementation approach was changed to locking, and the Less Invasive Stabilization System (LISS) plate was introduced as a result. Finally, a combination of both of these approaches has been used by introducing the Locking Compression Plate (LCP). Currently, precontoured LCPs are mainly used for bone fracture fixation. In parallel with structure and implementation techniques, numerous advances have occurred in biomaterials of the plates. Titanium and stainless steel alloys are now the most common biomaterials in production of orthopedic bone plates. However, regarding the biocompatibility, bioactivity and biodegradability characteristics of Mg alloys, Ta alloys, SMAs, carbon fiber composites and bioceramics, these materials are considered as potentially suitable for plates. However, due to poor mechanical properties, they have very limited applications. Therefore, further studies are required in future to solve these problems and make them feasible for heavy-duty bone plates.

Does metabolic compensation explain the majority of less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention?

Objective: We investigated to what extent changes in metabolic rate and composition of weight loss explained the less-than-expected weight loss in obese men and women during a diet-plus-exercise intervention. Design: 16 obese men and women (41 ± 9 years; BMI 39 ± 6 kg/m2) were investigated in energy balance before, after and twice during a 12-week VLED (565–650 kcal/day) plus exercise (aerobic plus resistance training) intervention. The relative energy deficit (EDef) from baseline requirements was severe (74-87%). Body composition was measured by deuterium dilution and DXA and resting metabolic rate (RMR) by indirect calorimetry. Fat mass (FM) and fat-free mass (FFM) were converted into energy equivalents using constants: 9.45 kcal/gFM and 1.13 kcal/gFFM. Predicted weight loss was calculated from the energy deficit using the '7700 kcal/kg rule'. Results: Changes in weight (-18.6 ± 5.0 kg), FM (-15.5 ± 4.3 kg), and FFM (-3.1 ± 1.9 kg) did not differ between genders. Measured weight loss was on average 67% of the predicted value, but ranged from 39 to 94%. Relative EDef was correlated with the decrease in RMR (R=0.70, P<0.01) and the decrease in RMR correlated with the difference between actual and expected weight loss (R=0.51, P<0.01). Changes in metabolic rate explained on average 67% of the less-than-expected weight loss, and variability in the proportion of weight lost as FM accounted for a further 5%. On average, after adjustment for changes in metabolic rate and body composition of weight lost, actual weight loss reached 90% of predicted values. Conclusion: Although weight loss was 33% lower than predicted at baseline from standard energy equivalents, the majority of this differential was explained by physiological variables. While lower-than-expected weight loss is often attributed to incomplete adherence to prescribed interventions, the influence of baseline calculation errors and metabolic down-regulation should not be discounted.