Linkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome)

Abstract Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.

Relationship between physical activity and stiff or painful joints in mid-aged women and older women: a 3-year prospective study

This prospective study examined the association between physical activity and the incidence of self-reported stiff or painful joints (SPJ) among mid-age women and older women over a 3-year period. Data were collected from cohorts of mid-age (48–55 years at Time 1; n = 4,780) and older women (72–79 years at Time 1; n = 3,970) who completed mailed surveys 3 years apart for the Australian Longitudinal Study on Women's Health. Physical activity was measured with the Active Australia questions and categorized based on metabolic equivalent value minutes per week: none (<40 MET.min/week); very low (40 to <300 MET.min/week); low (300 to <600 MET.min/week); moderate (600 to <1,200 MET.min/week); and high (1,200+ MET.min/week). Cohort-specific logistic regression models were used to examine the association between physical activity at Time 1 and SPJ 'sometimes or often' and separately 'often' at Time 2. Respondents reporting SPJ 'sometimes or often' at Time 1 were excluded from analysis. In univariate models, the odds of reporting SPJ 'sometimes or often' were lower for mid-age respondents reporting low (odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.63–0.94), moderate (OR = 0.82, 95% CI = 0.68–0.99), and high (OR = 0.75, 95% CI = 0.62–0.90) physical activity levels and for older respondents who were moderately (OR = 0.80, 95% CI = 0.65–0.98) or highly active (OR = 0.83, 95% CI = 0.69–0.99) than for those who were sedentary. After adjustment for confounders, these associations were no longer statistically significant. The odds of reporting SPJ 'often' were lower for mid-age respondents who were moderately active (OR = 0.71, 95% CI = 0.52–0.97) than for sedentary respondents in univariate but not adjusted models. Older women in the low (OR = 0.72, 95% CI = 0.55–0.96), moderate (OR = 0.54, 95% CI = 0.39–0.76), and high (OR = 0.61, 95% CI = 0.46–0.82) physical activity categories had lower odds of reporting SPJ 'often' at Time 2 than their sedentary counterparts, even after adjustment for confounders. These results are the first to show a dose–response relationship between physical activity and arthritis symptoms in older women. They suggest that advice for older women not currently experiencing SPJ should routinely include counseling on the importance of physical activity for preventing the onset of these symptoms.

Genetic and gene expression analyses of the polycystic ovary syndrome candidate gene fibrillin-3 and other fibrillin family members in human ovaries

Several studies have demonstrated an association between polycystic ovary syndrome (PCOS) and the dinucleotide repeat microsatellite marker D19S884, which is located in intron 55 of the fibrillin-3 (FBN3) gene. Fibrillins, including FBN1 and 2, interact with latent transforming growth factor (TGF)-β-binding proteins (LTBP) and thereby control the bioactivity of TGFβs. TGFβs stimulate fibroblast replication and collagen production. The PCOS ovarian phenotype includes increased stromal collagen and expansion of the ovarian cortex, features feasibly influenced by abnormal fibrillin expression. To examine a possible role of fibrillins in PCOS, particularly FBN3, we undertook tagging and functional single nucleotide polymorphism (SNP) analysis (32 SNPs including 10 that generate non-synonymous amino acid changes) using DNA from 173 PCOS patients and 194 controls. No SNP showed a significant association with PCOS and alleles of most SNPs showed almost identical population frequencies between PCOS and control subjects. No significant differences were observed for microsatellite D19S884. In human PCO stroma/cortex (n = 4) and non-PCO ovarian stroma (n = 9), follicles (n = 3) and corpora lutea (n = 3) and in human ovarian cancer cell lines (KGN, SKOV-3, OVCAR-3, OVCAR-5), FBN1 mRNA levels were approximately 100 times greater than FBN2 and 200–1000-fold greater than FBN3. Expression of LTBP-1 mRNA was 3-fold greater than LTBP-2. We conclude that FBN3 appears to have little involvement in PCOS but cannot rule out that other markers in the region of chromosome 19p13.2 are associated with PCOS or that FBN3 expression occurs in other organs and that this may be influencing the PCOS phenotype.

Manufacturing practices and performances: A Malaysian study

The purpose of this study is to identify the most common manufacturing practices adopted by the Malaysian manufacturers, company performance factors and relationship between practices and performances. To fulfil the study objectives, 400 manufacturers were surveyed by a standard 400 questionnaire. Three research methodologies such as descriptive analysis, ANOVA and regression analysis have been employed in this study. The analysis revealed that Malaysian manufacturers focus on optimizing three critical performance factors: product development, less customer return rate and on time delivery (OTD). The most important competitive factor was found to be company reputation and design and manufacturing capacity is the least important factor. The findings also proved that manufacturing practices significantly influence company performances

Partial agonists of the [alpha]3[beta]4[ast] neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats

Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors (nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the α3, α5, and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the α3, and β4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at α3β4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with their unbound rat brain concentrations, suggesting that the effects on ethanol self-administration are mediated via interaction with α3β4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with α3β4 nAChRs. Furthermore, the selective α4β2(*) nAChR antagonist, DHβE, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs.

Nitrone [2]rotaxanes: Simultaneous chemical protection and electrochemical activation of a functional group

We report on the use of the hydrogen bond accepting properties of neutral nitrone moieties to prepare benzylic-amide-macrocycle-containing [2]rotaxanes in yields as high as 70 %. X-Ray crystallography shows the presence of up to four intercomponent hydrogen bonds between the amide groups of the macrocycle and the two nitrone groups of the thread. Dynamic 1H NMR studies of the rates of macrocycle pirouetting in nonpolar solutions indicate that amide-nitrone hydrogen bonds are particularly strong, ~1.3 and ~0.2 kcal mol-1 stronger than similar amide-ester and amide-amide interactions, respectively. In addition to polarizing the N-O bond through hydrogen bonding, the rotaxane structure affects the chemistry of the nitrone groups in two significant ways: The intercomponent hydrogen bonding activates the nitrone groups to electrochemical reduction, a one electron reduction of the rotaxane being stablized by a remarkable 400 mV (8.1 kcal mol-1) with respect to the same process in the thread; encapsulation, however, protects the same functional groups from chemical reduction with an external reagent (and slows down electron transfer to and from the electroactive groups in cyclicvoltammetry experiments). Mechanical interlocking with a hydrogen bonding molecular sheath thus provides a route to an encapsulated polarized functional group and radical anions of significant kinetic and thermodynamic stability.

Early intervention music therapy : reporting on a 3-year project to address needs with at-risk families

Sing & Grow is an early intervention music therapy project presented to families with additional needs, or those at risk of experiencing disadvantage due to social and/or economic circumstances that may impact on their parenting experiences. The aim of the project is to provide short term music therapy programs to families in communities where access to such services may be limited. The program is strengths-based and focuses on building upon a parent’s capacity to relate to and respond to their child’s emotional and developmental needs.