Contribution of P2X4 receptor in pain associated with rheumatoid arthritis: a review

Purinergic Signalling - Pain is the most common symptom reported by patients with rheumatoid arthritis (RA) even after the resolution of chronic joint inflammation. It is believed that...     

Unmasking Heavily O-Glycosylated Serum Proteins Using Perchloric Acid: Identification of Serum Proteoglycan 4 and Protease C1 Inhibitor as Molecular Indicators for Screening of Breast Cancer

Heavily glycosylated mucin glycopeptides such as CA 27.29 and CA 15–3 are currently being used as biomarkers for detection and monitoring of breast cancer. However, they are not well detected at the early stages of the cancer. In the present study, perchloric acid (PCA) was used to enhance detection of mucin-type O-glycosylated proteins in the serum in an attempt to identify new biomarkers for early stage breast cancer. Sensitivity and specificity of an earlier developed sandwich enzyme-linked lectin assay were significantly improved with the use of serum PCA isolates. When a pilot case-control study was performed using the serum PCA isolates of normal participants (n = 105) and patients with stage 0 (n = 31) and stage I (n = 48) breast cancer, higher levels of total O-glycosylated proteins in sera of both groups of early stage breast cancer patients compared to the normal control women were demonstrated. Further analysis by gel-based proteomics detected significant inverse altered abundance of proteoglycan 4 and plasma protease C1 inhibitor in both the early stages of breast cancer patients compared to the controls. Our data suggests that the ratio of serum proteoglycan 4 to protease C1 inhibitor may be used for screening of early breast cancer although this requires further validation in clinically representative populations.     

Biomarker potential of C-peptide for screening of insulin resistance in diabetic and non-diabetic individuals

Insulin resistance is a hallmark feature of type-2 diabetes mellitus (T2DM). We determined the homeostatic model assessment insulin resistance (HOMA-IR) and evaluated its association with C-peptide, insulin, fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) in T2DM patients and non-diabetic subjects. This study comprised a total of 47 T2DM patients and 38 non-diabetic controls. Venous blood samples from all the subjects were collected and sera were analyzed for FBG, HbA1c, insulin and C-peptide using an autoanalyzer. HOMA-IR was calculated using the following equation: HOMA-IR?=?fasting insulin (µU/ml)?×?fasting glucose (mmol/L)/22.5. There was a significant increase in the levels of FBG and HbA1c in diabetic patients. Although the levels of C-peptide and insulin did not differ significantly between the two groups, a significant increase in HOMA-IR was observed in T2DM patients. Both insulin and C-peptide were significantly correlated with HOMA-IR. In conclusion, C-peptide may serve as a simple and convenient predictor of HOMA-IR.     

Interval time-place learning in young children

While previous research has investigated the ability of animals to learn the spatial and temporal contingencies of biologically significant events (known as time-place learning), this ability has not been studied in humans. Children ranging from 5 to 10 years old were tested on a modified interval time-place learning task using a touchscreen computer. Results demonstrate the children were able to quickly learn both the timing and the sequence of this task. Despite a lack of anticipation on baseline trials, the children continued to follow the spatio-temporal contingencies in probe sessions where these contingencies were removed. Performance on the probe sessions provide strong evidence that the children had learned the spatio-temporal contingencies. Future research is needed to determine what age-related changes in iTPL occur. Furthermore, it is argued that this procedure can be used to extend interval timing in research in children, including, but not limited to, investigation of scalar timing with longer durations than have previously been investigated.     

Mechanism of reduced colonic contractility in experimental colitis: role of sarcoplasmic reticulum pump isoform-2

Inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis are inflammatory disorders associated with decreased colonic contractility. Here we show that, in experimental colitis in rat induced by trinitrobenzenesulfonic acid, there is a decrease in contraction in response to carbamoylcholine and the sarco/endoplasmic reticulum Ca⁺² (SERCA) pump inhibitor thapsigargin. However, the decrease in contractility may occur due to decrease in the SERCA pump levels or their inactivation. Therefore, we examined the protein and mRNA levels for SERCA2 isoform, which is predominant isoform in colonic smooth muscle. There was a decrease in the levels of SERCA2 protein and mRNA levels in inflamed colonic muscle. These findings suggest that decreased SERCA pump levels is responsible for a decrease in the Ca⁺² stores in the sarco/endoplasmic reticulum that causes a decrease in the contractility in colonic smooth muscle leading to poor bowel movements.     

High Density Lipoprotein Stimulated Migration of Macrophages Depends on the Scavenger Receptor Class B,Type I,PDZK1 and Akt1 and Is Blocked by Sphingosine 1 Phosphate Receptor Antagonists

HDL carries biologically active lipids such as sphingosine-1-phosphate (S1P) and stimulates a variety of cell signaling pathways in diverse cell types, which may contribute to its ability to protect against atherosclerosis. HDL and sphingosine-1-phosphate receptor agonists, FTY720 and SEW2871 triggered macrophage migration. HDL-, but not FTY720-stimulated migration was inhibited by an antibody against the HDL receptor, SR-BI, and an inhibitor of SR-BI mediated lipid transfer. HDL and FTY720-stimulated migration was also inhibited in macrophages lacking either SR-BI or PDZK1, an adaptor protein that binds to SR-BI''s C-terminal cytoplasmic tail. Migration in response to HDL and S1P receptor agonists was inhibited by treatment of macrophages with sphingosine-1-phosphate receptor type 1 (S1PR1) antagonists and by pertussis toxin. S1PR1 activates signaling pathways including PI3K-Akt, PKC, p38 MAPK, ERK1/2 and Rho kinases. Using selective inhibitors or macrophages from gene targeted mice, we demonstrated the involvement of each of these pathways in HDL-dependent macrophage migration. These data suggest that HDL stimulates the migration of macrophages in a manner that requires the activities of the HDL receptor SR-BI as well as S1PR1 activity.     

Does the Axillary Lymph Node Ratio Have Any Added Prognostic Value over pN Staging for South East Asian Breast Cancer Patients?

Introduction

Lymph node ratio (LNR, i.e. the ratio of the number of positive nodes to the total number of nodes excised) is reported to be superior to the absolute number of nodes involved (pN stage) in classifying patients at high versus low risk of death following breast cancer. The added prognostic value of LNR over pN in addition to other prognostic factors has never been assessed.

Methods

All patients diagnosed with lymph node positive, non-metastatic invasive breast cancer at the National University Hospital (Singapore) and University of Malaya Medical Center (Kuala Lumpur) between 1990–2007 were included (n = 1589). Overall survival of the patients was estimated by the Kaplan Meier method for LNR [categorized as low (>0 and <0.2), intermediate (0.2–0.65) and high (>0.65–1)] and pN staging [pN1, pN2 and pN3]. Adjusted overall relative mortality risks associated with LNR and pN were calculated by Cox regression. The added prognostic value of LNR over pN was evaluated by comparing the discriminating capacity (as indicated by the c statistic) of two multivariate models, one including pN and one including LNR.

Results

LNR was superior to pN in categorizing mortality risks for women ≥60 years, those with ER negative or grade 3 tumors. In combination with other factors (i.e. age, treatment, grade, tumor size and receptor status), substituting pN by LNR did not result in better discrimination of women at high versus low risk of death, neither for the entire cohort (c statistic 0.72 [0.70–0.75] and 0.73 [0.71–0.76] respectively for pN versus LNR), nor for the subgroups mentioned above.

Conclusion

In combination with other prognosticators, substitution of pN by LNR did not provide any added prognostic value for South East Asian breast cancer patients.     

BRCA1 and BRCA2 germline mutations in Malaysian women with early-onset breast cancer without a family history

Background

In Asia, breast cancer is characterised by an early age of onset: In Malaysia, approximately 50% of cases occur in women under the age of 50 years. A proportion of these cases may be attributable, at least in part, to genetic components, but to date, the contribution of genetic components to breast cancer in many of Malaysia''s ethnic groups has not been well-characterised.

Methodology

Given that hereditary breast carcinoma is primarily due to germline mutations in one of two breast cancer susceptibility genes, BRCA1 and BRCA2, we have characterised the spectrum of BRCA mutations in a cohort of 37 individuals with early-onset disease (≤40 years) and no reported family history. Mutational analysis of BRCA1 and BRCA2 was conducted by full sequencing of all exons and intron-exon junctions.

Conclusions

Here, we report a total of 14 BRCA1 and 17 BRCA2 sequence alterations, of which eight are novel (3 BRCA1 and 5 BRCA2). One deleterious BRCA1 mutation and 2 deleterious BRCA2 mutations, all of which are novel mutations, were identified in 3 of 37 individuals. This represents a prevalence of 2.7% and 5.4% respectively, which is consistent with other studies in other Asian ethnic groups (4–9%).     

A triple bottom line evaluation of solid waste management strategies: a case study for an arid Gulf State,Kuwait

Purpose

We extend a life cycle assessment (LCA) embracing both economic and social perspectives to develop an integrated solid waste management system for Kuwait. This study considers the domestic waste generated by households and waste generated commercially. Six municipal solid waste (MSW) scenarios (SR₁, SR₂, …, SR₆) are evaluated using a triple bottom line (TBL) approach that incorporates environmental, financial, and social bottom lines (social BLs).

Methods

Within the TBL framework, the environmental BL employs LCA in accordance with ISO 14044. The financial BL is calculated using capital and operational costs as well as the associated recycling revenues. The social BL applies macro-economic indicators that examine the effects of a given MSW scenario (SR) on the inhabitants. To integrate the TBLs, we apply an analytic hierarchy process (AHP) because of its advantage of pairwise unit-free rescaling. The relative importance of each BL is determined by considering the political, legal, socio-cultural, and economic climates of the country. The relative weights are cross-multiplied with indicators from each BL to calculate a composite sustainability index (CSI) for the proposed MSW SR.

Results and discussion

The environmental BL (LCA) indicates that global warming, acidification, and human toxicity are the most adversely affected impact categories, considering the local conditions and waste composition. Environmentally, SR₁ (landfilling) scored the worst in almost all impact categories and, thus, was labeled the worst-case scenario environmentally. SR₆ (composting, recycling, and incineration) performed the best from an environmental perspective. Financially, landfilling (SR₁) is the most economical scenario. Any SR that focused on incineration (SR₂ and SR₅) was financially unfavorable. The scenarios that involved composting were scored as financially reasonable (SR₃, SR₄, and SR₆). From a social acceptability perspective, SR₂ (incineration) scored the highest, while SR₁ (landfills) scored the lowest. Finally, across the TBL framework, SR₄ (composting and incineration) had the highest CSI based on the relative importance scheme adopted for each BL.

Conclusions

Although they are often overlooked in most LCA studies, the financial and social aspects are indispensable to proving feasibility and credibility at a strategic level. The complexity of financial and social formulations in LCA is inherited from the difficulty in quantifying emissions and other impacts. In addition, from a social perspective, the contingent risks and associated uncertainty vary widely across cultures, ideologies, and degrees of development and are further complicated because of the scarcity and uncertainty of the data.