Serum bone formation marker correlation with improved osseointegration in osteoporotic rats treated with simvastatin

Objective: Simvastatin has been shown to enhance osseointegration of pure titanium implants in osteoporotic rats. This study aimed to evaluate the relationship between the serum level of bone formation markers and the osseointegration of pure titanium implants in osteoporotic rats treated with simvastatin. Materials and methods: Fifty-four female Sprague Dawley rats, aged 3 months old, were randomly divided into three groups: Sham-operated group (SHAM; n=18), ovariectomized group (OVX; n=18), and ovariectomized with Simvastatin treatment group (OVX+SIM; n=18). Fifty-six days after ovariectomy, screw-shaped titanium implants were inserted into the tibiae. Simvastatin was administered orally at 5mg/kg each day after the placement of the implant in the OVX+SIM group. The animals were sacrificed at either 28 or 84 days after implantation and the undecalcified tissue sections were processed for histological analysis. Total alkaline phosphatase (ALP), bone specific alkaline phosphatase (BALP) and bone Gla protein (BGP) were measured in all animal sera collected at the time of euthanasia and correlated with the histological assessment of osseointegration. Results: The level of ALP in the OVX group was higher than the SHAM group at day 28, with no differences between the three groups at day 84. The level of BALP in the OVX+SIM group was significantly higher than both OVX and SHAM groups at days 28 and 84. Compared with day 28, the BALP level of all three groups showed a significant decrease at day 84. There were no significant differences in BGP levels between the three groups at day 28, but at day 84 the OVX+SIM group showed significantly higher levels than both the OVX and SHAM groups. There was a significant increase in BGP levels between days 28 and 84 in the OVX+SIM group. The serum bone marker levels correlated with the histological assessment showing reduced osseointegration in the OVX compared to the SHAM group which is subsequently reversed in the OVX+SIM group.

Biomaterial scaffolds in cartilage-subchondral bone defects influencing the repair of autologous articular cartilage transplants

The repair of articular cartilage typically involves the repair of cartilage-subchondral bone tissue defects. Although various bioactive materials have been used to repair bone defects, how these bioactive materials in subchondral bone defects influence the repair of autologous cartilage transplant remains unclear. The aim of this study was to investigate the effects of different subchondral biomaterial scaffolds on the repair of autologous cartilage transplant in a sheep model. Cylindrical cartilage-subchondral bone defects were created in the right femoral knee joint of each sheep. The subchondral bone defects were implanted with hydroxyapatite-β-tricalcium phosphate (HA-TCP), poly lactic-glycolic acid (PLGA)-HA-TCP dual-layered composite scaffolds (PLGA/HA-TCP scaffolds), or autologous bone chips. The autologous cartilage layer was placed on top of the subchondral materials. After three months, the effect of different subchondral scaffolds on the repair of autologous cartilage transplant was systematically studied by investigating the mechanical strength, structural integration and histological responses. The results showed that the transplanted cartilage layer supported by HA-TCP scaffolds had better structural integration and higher mechanical strength than that supported by PLGA/HA-TCP scaffolds. Furthermore, HA-TCP supported cartilage showed higher expression of acid mucosubstances and glycol-amino-glycan (GAG) contents than that supported by PLGA/HA-TCP scaffolds. Our results suggested that the physicochemical properties, including the inherent mechanical strength and material chemistry of the scaffolds, play important roles in influencing the repair of autologous cartilage transplants. The study may provide useful information for the design and selection of proper subchondral biomaterials to support the repair of both subchondral bone and cartilage defects.

The influence of glass types on the performance of air-conditioned office buildings in Australia

Windows are one of the most significant elements in the design of buildings. Whether there are small punched openings in the facade or a completely glazed curtain wall, windows are usually a dominant feature of the building's exterior appearance. From the energy use perspective, windows may also be regarded as thermal holes for a building. Therefore, window design and selection must take both aesthetics and serviceability into consideration. In this paper, using building computer simulation techniques, the effects of glass types on the thermal and energy performance of a sample air-conditioned office building in Australia are studied. It is found that a glass type with lower shading coefficient will have a lower building cooling load and total energy use. Through the comparison of results between current and future weather scenarios, it is identified that the pattern found from the current weather scenario would also exist in the future weather scenario, although the scale of change would become smaller. The possible implication of glazing selection in face of global warming is also examined. It is found that compared with its influence on building thermal performance, its influence on the building energy use is relatively small or insignificant.

Verbal instruction abolishes fear conditioned to racial out-group faces

Previous research has shown resistance to extinction of fear conditioned to racial out-group faces, suggesting that these stimuli may be subject to prepared fear learning. The current study replicated and extended previous research by using a different racial out-group, and testing the prediction that prepared fear learning is unaffected by verbal instructions. Four groups of Caucasian participants were trained with male in-group (Caucasian) or out-group (Chinese) faces as conditional stimuli; one paired with an electro-tactile shock (CS+) and one presented alone (CS). Before extinction, half the participants were instructed that no more shocks would be presented. Fear conditioning, indexed by larger electrodermal responses to, and blink startle modulation during the CS+, occurred during acquisition in all groups. Resistance to extinction of fear learning was found only in the racial out-group, no instruction condition. Fear conditioned to a racial out-group face was reduced following verbal instructions, contrary to predictions for the nature of prepared fear learning.

On the resistance to extinction of fear conditioned to angry faces

The present study investigated whether, like fear conditioned to pictures of snakes and spiders, fear conditioned to angry faces resists extinction even after verbal instruction and removal of the shock electrode. Participants were trained in a differential Pavlovian fear conditioning procedure with angry face or happy face conditional stimuli (CSs). Prior to extinction, half the participants in each group were informed that no more unconditional stimuli would be presented and the shock electrode was removed. In the absence of this manipulation, participants showed resistance to extinction after training with angry face CSs, but not after training with happy face CSs. Instructed extinction and electrode removal abolished fear conditioning regardless of the emotion expressed by the CS faces. This finding suggests that fear conditioned to angry faces, like fear conditioned to racial out-group faces, is more malleable than fear conditioned to snakes and spiders.

The expression, regulation and function of kallikrein 4 in prostate cancer

Prostate cancer is a significant health problem faced by aging men. Currently, diagnostic strategies for the detection of prostate cancer are either unreliable, yielding high numbers of false positive results, or too invasive to be used widely as screening tests. Furthermore, the current therapeutic strategies for the treatment of the disease carry considerable side effects. Although organ confined prostate cancer can be curable, most detectable clinical symptoms occur in advanced disease when primary tumour cells have metastasised to distant sites - usually lymph nodes and bone. Many growth factors and steroids assist the continued growth and maintenance of prostatic tumour cells. Of these mitogens, androgens are important in the development of the normal prostate but are also required to sustain the growth of prostate cancer cells in the early stage of the disease. Not only are androgens required in the early stage of disease, but also many other growth factors and hormones interact to cause uncontrolled proliferation of malignant cells. The early, androgen sensitive phase of disease is followed by an androgen insensitive phase, whereby androgens are no longer required to stimulate the growth of the tumour cells. Growth factors such as transforming growth factor  and  (TGF/), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin-like growth factors (IGFs), Vitamin D and thyroid hormone have been suggested to be important at this stage of disease. Interestingly, some of the kallikrein family of genes, including prostate specific antigen (PSA), the current serum diagnostic marker for prostate cancer, are regulated by androgens and many of the aforementioned growth factors. The kallikrein gene family is a group of serine proteases that are involved in a diverse range of physiological processes: regulation of local blood flow, angiogenesis, tissue invasion and mitogenesis. The earliest members of the kallikrein gene family (KLK1-KLK3) have been strongly associated with general disease states, such as hypertension, inflammation, pancreatitis and renal disease, but are also linked to various cancers. Recently, this family was extended to include 15 genes (KLK1-15). Several newer members of the kallikrein family have been implicated in the carcinogenesis and tumour metastasis of hormone-dependent cancers such as prostate, breast, endometrial and ovarian cancer. The aims of this project were to investigate the expression of the newly identified kallikrein, KLK4, in benign and malignant prostate tissues, and prostate cancer cell lines. This thesis has demonstrated the elevated expression of KLK4 mRNA transcripts in malignant prostate tissue compared to benign prostates. Additionally, expression of the full length KLK4 transcript was detected in the androgen dependent prostate cancer cell line, LNCaP. Based on the above finding, the LNCaP cell line was chosen to assess the potential regulation of full length KLK4 by androgen, thyroid hormone and epidermal growth factor. KLK4 mRNA and protein was found to be up-regulated by androgen and a combination of androgen and thyroid hormone. Thyroid hormone alone produced no significant change in KLK4 mRNA or protein over the control. Epidermal growth factor treatment also resulted in elevated expression levels of KLK4 mRNA and protein. To assess the potential functional role(s) of KLK4/hK4 in processes associated with tumour progression, full length KLK4 was transfected into PC-3 cells - a prostate cancer cell line originally derived from a secondary bone lesion. The KLK4/hK4 over-expressing cells were assessed for their proliferation, migration, invasion and attachment properties. The KLK4 over-expressing clones exhibited a marked change in morphology, indicative of a more aggressive phenotype. The KLK4 clones were irregularly shaped with compromised adhesion to the growth surface. In contrast, the control cell lines (parent PC-3 and empty vector clones) retained a rounded morphology with obvious cell to cell adhesion, as well as significant adhesion to their growth surface. The KLK4 clones exhibited significantly greater attachment to Collagen I and IV than native PC-3s and empty vector controls. Over a 12 hour period, in comparison to the control cells, the KLK4 clones displayed an increase in migration towards PC-3 native conditioned media, a 3 fold increase towards conditioned media from an osteoblastic cell line (Saos-2) and no change in migration towards conditioned media from neonatal foreskin fibroblast cells or 20% foetal bovine serum. Furthermore, the increase in migration exhibited by the KLK4 clones was partially blocked by the serine protease inhibitor, aprotinin. The data presented in this thesis suggests that KLK4/hK4 is important in prostate carcinogenesis due to its over-expression in malignant prostate tissues, its regulation by hormones and growth factors associated with prostate disease and the functional consequences of over-expression of KLK4/hK4 in the PC-3 cell line. These results indicate that KLK4/hK4 may play an important role in tumour invasion and bone metastasis via increased attachment to the bone matrix protein, Collagen I, and enhanced migration due to soluble factors produced by osteoblast cells. This suggestion is further supported by the morphological changes displayed by the KLK4 over-expressing cells. Overall, this data suggests that KLK4/hK4 should be further studied to more fully investigate the potential value of KLK4/hK4 as a diagnostic/prognostic biomarker or in therapeutic applications.

Energy use, indoor temperature and possible adaptation strategies for air-conditioned office buildings in face of global warming

This paper discusses and summarises a recent systematic study on the implication of global warming on air conditioned office buildings in Australia. Four areas are covered, including analysis of historical weather data, generation of future weather data for the impact study of global warming, projection of building performance under various global warming scenarios, and evaluation of various adaptation strategies under 2070 high global warming conditions. Overall, it is found that depending on the assumed future climate scenarios and the location considered, the increase of total building energy use for the sample Australian office building may range from 0.4 to 15.1%. When the increase of annual average outdoor temperature exceeds 2 °C, the risk of overheating will increase significantly. However, the potential overheating problem could be completely eliminated if internal load density is significantly reduced.

Impact of global warming on the design and performance of air-conditioned office buildings in Australia

As global warming entails new conditions for the built environment, the thermal behavior of existing air conditioned office buildings, which are typically designed based on current weather data, may also change. Through building computer simulations, this paper evaluates the impact of global warming on the design and performance of air-conditioned office buildings in Australia, including the increased cooling loads imposed by potential global warming and probable indoor temperature increases due to possible undersized air-conditioning system, as well as the possible change in energy use and CO2 emission of Australian office buildings. It is found that the existing office buildings would generally be able to adapt to the increasing warmth of 2030 year Low and High scenarios projections and 2070 year Low scenario projection. However, for the 2070 year High scenario, the study indicates that the existing office buildings, in all capital cities except for Hobart, will suffer from overheating problems. If the energy source is assumed to be the electricity, it is found that in comparison with current weather scenario, the increased energy uses would translate into the increase of CO2 emissions by 0 to 34.6 kg CO2 equivalent/m2, varying with different future weather scenarios and with different locations.

Serum YKL-40 and Interleukin 6 Levels in Hodgkin Lymphoma

Purpose Serum levels of the inflammatory markers YKL-40 and IL-6 are increased in many conditions, including cancers. We examined serum YKL-40 and IL-6 levels in patients with Hodgkin lymphoma (HL), a tumor with strong immunologic reaction to relatively few tumor cells, especially in nodular sclerosis HL. Experimental Design We analyzed Danish and Swedish patients with incident HL (N=470) and population controls from Denmark (N= 245 for YKL-40; N= 348 for IL-6). Serum YKL-40 and IL-6 levels were determined by ELISA, and log-transformed data were analysed by linear regression, adjusting for age and sex. Results Serum levels of YKL-40 and IL-6 were increased in HL patients compared to controls (YKL-40: 3.6-fold, IL-6: 8.3-fold; both p<0.0001). In samples from pre-treatment HL patients (N=176), levels were correlated with more advanced stages (ptrend 0.0001 for YKL-40 and 0.013 for IL-6) and in those with B symptoms, but levels were similar in nodular sclerosis and mixed cellularity subtypes, by EBV status, and in younger (<45 years old) and older patients. Patients tested soon after treatment onset had significantly lower levels than pre-treatment patients, but even >6 months after treatment onset, serum YKL-40 and IL-6 levels remained significantly increased, compared to controls. In patients who died (N=12), pre-treatment levels for both YKL-40 and IL-6 were higher than in survivors, although not statistically significantly. Conclusions Serum YKL-40 and IL-6 levels were increased in untreated HL patients and those with more advanced stages but did not differ significantly by HL histology. Following treatment, serum levels were significantly lower.

Human proximal tubule epithelial cells modulate autologous dendritic cell function

Background We have previously demonstrated that human kidney proximal tubule epithelial cells (PTEC) are able to modulate autologous T and B lymphocyte responses. It is well established that dendritic cells (DC) are responsible for the initiation and direction of adaptive immune responses and that these cells occur in the renal interstitium in close apposition to PTEC under inflammatory disease settings. However, there is no information regarding the interaction of PTEC with DC in an autologous human context. Methods Human monocytes were differentiated into monocyte-derived DC (MoDC) in the absence or presence of primary autologous activated PTEC and matured with polyinosinic:polycytidylic acid [poly(I:C)], while purified, pre-formed myeloid blood DC (CD1c+ BDC) were cultured with autologous activated PTEC in the absence or presence of poly(I:C) stimulation. DC responses were monitored by surface antigen expression, cytokine secretion, antigen uptake capacity and allogeneic T-cell-stimulatory ability. Results The presence of autologous activated PTEC inhibited the differentiation of monocytes to MoDC. Furthermore, MoDC differentiated in the presence of PTEC displayed an immature surface phenotype, efficient phagocytic capacity and, upon poly(I:C) stimulation, secreted low levels of pro-inflammatory cytokine interleukin (IL)-12p70, high levels of anti-inflammatory cytokine IL-10 and induced weak Th1 responses. Similarly, pre-formed CD1c+ BDC matured in the presence of PTEC exhibited an immature tolerogenic surface phenotype, strong endocytic and phagocytic ability and stimulated significantly attenuated T-cell proliferative responses. Conclusions Our data suggest that activated PTEC regulate human autologous immunity via complex interactions with DC. The ability of PTEC to modulate autologous DC function has important implications for the dampening of pro-inflammatory immune responses within the tubulointerstitium in renal injuries. Further dissection of the mechanisms of PTEC modulation of autologous immune responses may offer targets for therapeutic intervention in renal medicine.

The utility of serum CA-125 in predicting extra-uterine disease in apparent early stage endometrial cancer

Objectives: To evaluate the clinical value of pre-operative serum CA125 in predicting the presence of extra-uterine disease in patients with apparent early stage endometrial cancer. Methods: Between October 6, 2005 and June 17, 2010, 760 patients were enrolled in an international, multicentre, prospective randomized trial (LACE) comparing laparotomy with laparoscopy in the management of endometrial cancer apparently confined to the uterus. This study is based on data from 657 patients with endometrial adenocarcinoma who had a pre-operative serum CA125 value, and was undertaken to correlate pre-operative serum CA125 with final stage. Results: Using a pre-operative CA-125 cutpoint of 30U/ml was associated with the smallest misclassification error (14.5%) using a multiple cross-validation method. Median pre-operative serum CA-125 was 14U/ml, and using a cutpoint of 30U/ml, 14.9% of patients had elevated CA-125 levels. Of 98 patients with elevated CA-125 level, 36 (36.7%) had evidence of extra-uterine disease. Of the 116 patients (17.7%) with evidence of extra-uterine disease, 31.0% had elevated CA-125 level. In univariate and multivariate logistic regression analysis, only pre-operative CA-125 level was found to be associated with extra-uterine spread of disease. Utilising a cutpoint of 30U/ml achieved a sensitivity, specificity, positive predictive value and negative predictive value of 31.0%, 88.5%, 36.7% and 85.7% respectively. Overall, 326/657 (49.6%) of patients had full surgical staging involving lymph node dissection. When analysis was limited to patients that had undergone full surgical staging, the outcomes remained essentially unchanged. Conclusions: Elevated CA-125 above 30U/ml in patients with apparent early stage disease is associated with a sensitivity of 31.0% and specificity of 88.5% in detecting extra-uterine disease. Pre-operative identification of this risk factor may assist to triage patients to tertiary centres and comprehensive surgical staging.

Partitioning of persistent organic pollutants (POPs) between human serum and breast milk : a literature review

The literature was reviewed to assess the relationship between the lipid adjusted concentration in human serum and breast milk (expressed as the serum/milk ratio) of a broad range of POPs in paired samples. Thirteen studies were identified, including seven studies that reported serum/milk ratios for polychlorinated dibenzo-dioxins and -furans (PCDD/Fs), ten for polychlorinated biphenyls (PCBs), five for polybrominated diphenyl ethers (PBDEs), and five for organochlorine pesticides (OCPs). Mean serum/milk ratios ranged between 0.7 and 25 depending on the compound and congener. For PCDD/Fs, PCBs and PBDEs, a clear trend of increasing mean serum/milk ratio by increasing molar volume, hydrophobicity and number of halogen substitutes was observed. The mean serum/milk ratios reported by the 13 studies summarized here will aid comparison between human POPs exposure studies using either serum or milk samples. More studies are needed to allow a valid comparison between data obtained from analysis of breast milk and serum samples for a broader range of POPs. Furthermore such studies may shed light on compound specific factors as well as other determinants that may affect the partitioning and partition kinetics of POPs between serum and breast milk.

Permeability estimation conditioned to geophysical downhole log data in sandstones of the northern Galilee Basin, Queensland : methods and application

This study uses borehole geophysical log data of sonic velocity and electrical resistivity to estimate permeability in sandstones in the northern Galilee Basin, Queensland. The prior estimates of permeability are calculated according to the deterministic log–log linear empirical correlations between electrical resistivity and measured permeability. Both negative and positive relationships are influenced by the clay content. The prior estimates of permeability are updated in a Bayesian framework for three boreholes using both the cokriging (CK) method and a normal linear regression (NLR) approach to infer the likelihood function. The results show that the mean permeability estimated from the CK-based Bayesian method is in better agreement with the measured permeability when a fairly apparent linear relationship exists between the logarithm of permeability and sonic velocity. In contrast, the NLR-based Bayesian approach gives better estimates of permeability for boreholes where no linear relationship exists between logarithm permeability and sonic velocity.