Evidence for Sodium-Coupled Acid-Base Transport Across the Basolateral Membrane of the Reabsorptive Duct of the Human Eccrine Sweat Gland

Intracellular pH was measured in isolated nonperfused ducts of human eccrine sweat glands in vitro to investigate basolateral acid-base transport mechanisms. Bath sodium removal led to a bicarbonate-independent, 4-acetamido-4′-isothiocyanatostilbene-2,2′-disulfonic acid insensitive acidification. The recovery of this acidification was ethylisopropyl amiloride sensitive, suggestive of basolateral sodium:hydrogen exchange. Whereas bath chloride removal led to a small acidification this was not 4-acetamido-4′-isothiocyanatostilbene-2,2′-disulfonic acid sensitive and its causes remain unclear. Elevation of bath potassium to depolarize the basolateral membrane led to a small alkalinization but this was not mimicked by addition of barium or chloride removal. As chloride removal and barium addition would be expected to cause larger depolarizations than potassium elevation these observations do not support a major role for electrogenic acid-base transport. In conclusion, although this study does not support a major role for electrogenic acid-base transport, it has demonstrated the basolateral presence of sodium-coupled acid-base transport in the reabsorptive duct of the human eccrine sweat gland, which most likely represents a sodium:hydrogen exchanger involved in regulation of intracellular pH

Australian women's use of complementary and alternative medicines to enhance fertility: exploring the experiences of women and practitioners

<p>Abstract</p> <p>Background</p> <p>Studies exploring the use of complementary and alternative medicine (CAM) to enhance fertility are limited. While Australian trends indicate that women are using CAM during pregnancy, little is known about women's use of CAM for fertility enhancement. With the rising age of women at first birth, couples are increasingly seeking assisted reproductive technologies (ART) to achieve parenthood. It is likely that CAM use for fertility enhancement will also increase, however this is not known. This paper reports on an exploratory study of women's use of CAM for fertility enhancement.</p> <p>Methods</p> <p>Three focus groups were conducted in Melbourne, Australia in 2007; two with women who used CAM to enhance their fertility and one with CAM practitioners. Participants were recruited from five metropolitan Melbourne CAM practices that specialise in women's health. Women were asked to discuss their views and experiences of both CAM and ART, and practitioners were asked about their perceptions of why women consult them for fertility enhancement. Groups were digitally recorded (audio) and transcribed verbatim. The data were analysed thematically.</p> <p>Results</p> <p>Focus groups included eight CAM practitioners and seven women. Practitioners reported increasing numbers of women consulting them for fertility enhancement whilst also using ART. Women combined CAM with ART to maintain wellbeing and assist with fertility enhancement. Global themes emerging from the women's focus groups were: women being willing to 'try anything' to achieve a pregnancy; women's negative experiences of ART and a reluctance to inform their medical specialist of their CAM use; and conversely, women's experiences with CAM being affirming and empowering.</p> <p>Conclusions</p> <p>The women in our study used CAM to optimise their chances of achieving a pregnancy. Emerging themes suggest the positive relationships achieved with CAM practitioners are not always attained with orthodox medical providers. Women's views and experiences need to be considered in the provision of fertility services, and strategies developed to enhance communication between women, medical practitioners and CAM practitioners. Further research is needed to investigate the extent of CAM use for fertility enhancement in Australia, and to explore the efficacy and safety of CAM use to enhance fertility, in isolation or with ART.</p

Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

ArrayExpress update--from an archive of functional genomics experiments to the atlas of gene expression

ArrayExpress http://www.ebi.ac.uk/arrayexpress consists of three components: the ArrayExpress Repository--a public archive of functional genomics experiments and supporting data, the ArrayExpress Warehouse--a database of gene expression profiles and other bio-measurements and the ArrayExpress Atlas--a new summary database and meta-analytical tool of ranked gene expression across multiple experiments and different biological conditions. The Repository contains data from over 6000 experiments comprising approximately 200,000 assays, and the database doubles in size every 15 months. The majority of the data are array based, but other data types are included, most recently-ultra high-throughput sequencing transcriptomics and epigenetic data. The Warehouse and Atlas allow users to query for differentially expressed genes by gene names and properties, experimental conditions and sample properties, or a combination of both. In this update, we describe the ArrayExpress developments over the last two years.</p