The <Emphasis Type="Italic">SLC2A9</Emphasis> nonsynonymous Arg265His variant and gout: evidence for a population-specific effect on severity

Introduction  

The C allele of the nonsynonymous Arg265His (rs3733591) variant of SLC2A9 confers risk for gout in Han Chinese, Solomon Island and Japanese samples, with a stronger role in tophaceous gout. There is no evidence for an association with gout in Caucasian populations. In the present study, we tested rs3733591 for association with gout in New Zealand (NZ) Māori, Pacific Island and Caucasian samples.     

Differential effects of age,cytomegalovirus-seropositivity and end-stage renal disease (ESRD) on circulating T lymphocyte subsets

The age- and cytomegalovirus (CMV)-seropositivity-related changes in subsets and differentiation of circulating T cells were investigated in end-stage renal disease (ESRD) patients (n = 139) and age-matched healthy individuals. The results show that CMV-seropositivity is associated with expansion of both CD4⁺ and CD8⁺ memory T cells which is already observed in young healthy individuals. In addition, CMV-seropositive healthy individuals have a more differentiated memory T cell profile. Only CMV-seropositive healthy individuals showed an age-dependent decrease in CD4⁺ naïve T cells. The age-related decrease in the number of CD8⁺ naïve T cells was CMV-independent. In contrast, all ESRD patients showed a profound naïve T-cell lymphopenia at every decade. CMV-seropositivity aggravated the contraction of CD4⁺ naïve T cells and increased the number of differentiated CD4⁺ and CD8⁺ memory T cells. In conclusion, CMV-seropositivity markedly alters the homeostasis of circulating T cells in healthy individuals and aggravates the T cell dysregulation observed in ESRD patients.     

Fused thiophene derivatives as MEK inhibitors

A number of novel fused thiophene derivatives have been prepared and identified as potent inhibitors of MEK. The SAR data of selected examples and the in vivo profiling of compound 13 h demonstrates the functional activity of this class of compounds in HT-29 PK/PD models.     

Analysis of the DISC1 translocation partner (11q14.3) in genetic risk of schizophrenia

The Disrupted‐in‐Schizophrenia 1 (DISC1) locus on human chromosome 1 was identified as a consequence of its involvement in a balanced translocation (1;11)(q42.1;q14.3) segregating with major psychiatric disorders in a Scottish family. Recently a comprehensive meta‐analysis of genome‐wide association scan data found no evidence that common variants of DISC1 (1q42.1) are associated with schizophrenia. Our aim was to test for association of variants in the 11q14.3 translocation region with schizophrenia. The 11q14.3 region was examined by meta‐analysis of genome‐wide scan data made available by the Genetic Association Information Network (GAIN) and other investigators (non‐GAIN) through dbGap. P‐values were adjusted for multiple testing using the false discovery rate (FDR) approach. There were no single‐nucleotide polymorphisms (SNPs) significant (P < 0.05) after correction for multiple testing in the combined schizophrenia dataset. However, one SNP (rs2509382) was significantly associated in the male‐only analysis with P_FDR = 0.024. Whilst the relevance of the (1;11)(q42.1;q14.3) translocation to psychiatric disorders is currently specific to the Scottish family, genetic material in the chromosome 11 region may contain risk variants for psychiatric disorders in the wider population. The association found in this region does warrant follow‐up analysis in further sample sets .     

2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase)

This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor.     

Novel non-viral method for transfection of primary leukemia cells and cell lines

BACKGROUND: Tumor cells such as leukemia and lymphoma cells are possible targets for gene therapy. However, previously leukemia and lymphoma cells have been demonstrated to be resistant to most of non-viral gene transfer methods. METHODS: The aim of this study was to analyze various methods for transfection of primary leukemia cells and leukemia cell lines and to improve the efficiency of gene delivery. Here, we evaluated a novel electroporation based technique called nucleofection. This novel technique uses a combination of special electrical parameters and specific solutions to deliver the DNA directly to the cell nucleus under mild conditions. RESULTS: Using this technique for gene transfer up to 75% of primary cells derived from three acute myeloid leukemia (AML) patients and K562 cells were transfected with the green flourescent protein (GFP) reporter gene with low cytotoxicity. In addition, 49(+/- 9.7%) of HL60 leukemia cells showed expression of GFP. CONCLUSION: The non-viral transfection method described here may have an impact on the use of primary leukemia cells and leukemia cell lines in cancer gene therapy.     

Sugar Sweetened Beverage Consumption among Adults with Gout or Type 2 Diabetes

Background

Current guidelines for the management of type 2 diabetes and gout recommend that people with these conditions limit their sugar sweetened beverage (SSB) intake. We examined self-reported SSB intake among New Zealand adults with gout or type 2 diabetes, including those on hemodialysis.

Method

1023 adults with gout and 580 adults (including 206 receiving hemodialysis) with type 2 diabetes, participated in this study of between 2009 and 2012. Participants completed an interviewer-administered SSB intake question “how many sugar sweetened drinks (including fruit juice), but not including diet drinks, do you normally drink per day?” SSB consumption was recorded as a circled number 0, 1, 2, 3, 4, 5, or >5, cans or large glasses (300mL) per day.

Results

Consuming one or more SSB per day was reported by 64% (622/1023) of subjects with gout, 49% (176/374) with type 2 diabetes without dialysis, and 47% (96/206) with diabetes on dialysis. Consuming four or more SSBs per day was reported by 18% (179/1023), 9% (31/374) and 9% (18/206), respectively. Such high consumers of SSB were characterized after multivariable analysis to be more likely to be male (adjusted odds ratio (OR) 1.8; 95% confidence interval 1.1–2.9), younger in age (40 vs 65 years: 1.6; 1.1–2.3), current smoker (5.2; 2.7–10.1), obese (BMI 41 vs 26kg/m²: 1.4; 1–1.9), and report Māori (1.8; 1.2–2.8) or Pacific (1.6; 1.1–2.5) ancestry, compared to Caucasian. People with gout were more likely to report heavy SSB intake compared to people with diabetes (OR 2.4, 95% CI 1.5–3.9). Heavy SSB consumption reported by people with diabetes was similar if they did or did not require dialysis.

Conclusion

A high proportion of patients with gout and type 2 diabetes, including those on haemodialysis, are not responding to health messages to abstain from SSB consumption.