The role of the gastrointestinal tract in phosphate homeostasis in health and chronic kidney disease.

For a number of years, there has been increasing interest in the concept of directly targeting intestinal phosphate transport to control hyperphosphatemia in chronic kidney disease. However, progress has been slow due to the paucity of information on the mechanisms involved in intestinal phosphate absorption. This editorial highlights the most recent developments in our understanding of this process and the role of the intestine in the maintenance of phosphate balance

Post-prandial adjustments in renal phosphate excretion do not involve a gut-derived phosphaturic factor

To date, the role of the small intestine in regulating post-prandial phosphate homeostasis has remained unclear and controversial. Previous studies have proposed the presence of a gut-derived phosphaturic factor that acts independently of changes in plasma phosphate concentration or parathyroid hormone (PTH) level; however, these early studies used duodenal luminal phosphate concentrations in the molar range and therefore the physiological relevance of this is uncertain. In the present study, we used both in vivo and in vitro approaches to investigate the presence of this putative ‘intestinal phosphatonin’. Instillation of 1.3M phosphate into the duodenum rapidly induced phosphaturia, but in contrast to previous reports, this was associated with significant hyperphosphataemia and elevated PTH level; however, there was not the expected decrease in abundance of the renal sodium-phosphate cotransporter NaPi-IIa. Instillation of a physiological (10mM) phosphate load had no effect on plasma phosphate concentration, PTH level or phosphate excretion. Moreover, phosphate uptake by opossum kidney cells was unaffected after incubation with serosal fluid collected from intestinal segments perfused with different phosphate concentrations. Taken together, these findings do not support the concept of a gut-derived phosphaturic factor that can mediate rapid signalling between gut and kidney, leading to increased urinary phosphate excretion, as part of normal phosphate homeostasis

Experimental and regional variations in Na+-dependent and Na+-independent phosphate transport along the rat small intestine and colon

Despite the importance of extracellular phosphate in many essential biological processes, the mechanisms of phosphate transport across the epithelium of different intestinal segments remain unclear. We have used an in vitro method to investigate phosphate transport at the brush border membrane (BBM) of intact intestinal segments and an in vivo method to study transepithelial phosphate absorption. We have used micromolar phosphate concentrations known to favor NaPi-IIb-mediated transport, and millimolar concentrations that are representative of the levels we have measured in luminal contents, to compare the extent of Na(+)-dependent and Na(+)-independent phosphate transport along the rat duodenum, jejunum, ileum, and proximal and distal colon. Our findings confirm that overall the jejunum is the main site of phosphate absorption; however, at millimolar concentrations, absorption shows ~30% Na(+)-dependency, suggesting that transport is unlikely to be mediated exclusively by the Na(+)-dependent NaPi-IIb co-transporter. In the ileum, studies in vitro confirmed that relatively low levels of phosphate transport occur at the BBM of this segment, although significant Na(+)-dependent transport was detected using millimolar levels of phosphate in vivo. Since NaPi-IIb protein is not detectable at the rat ileal BBM, our data suggest the presence of an as yet unidentified Na(+)-dependent uptake pathway in this intestinal segment in vivo. In addition, we have confirmed that the colon has a significant capacity for phosphate absorption. Overall, this study highlights the complexities of intestinal phosphate absorption that can be revealed using different phosphate concentrations and experimental techniques

Metric-based vs peer-reviewed evaluation of a research output: Lesson learnt from UK’s national research assessment exercise

Purpose There is a general inquisition regarding the monetary value of a research output, as a substantial amount of funding in modern academia is essentially awarded to good research presented in the form of journal articles, conferences papers, performances, compositions, exhibitions, books and book chapters etc., which, eventually leads to another question if the value varies across different disciplines. Answers to these questions will not only assist academics and researchers, but will also help higher education institutions (HEIs) make informed decisions in their administrative and research policies. Design and methodology To examine both the questions, we applied the United Kingdom’s recently concluded national research assessment exercise known as the Research Excellence Framework (REF) 2014 as a case study. All the data for this study is sourced from the openly available publications which arose from the digital repositories of REF’s results and HEFCE’s funding allocations. Findings A world leading output earns between £7504 and £14,639 per year within the REF cycle, whereas an internationally excellent output earns between £1876 and £3659, varying according to their area of research. Secondly, an investigation into the impact rating of 25315 journal articles submitted in five areas of research by UK HEIs and their awarded funding revealed a linear relationship between the percentage of quartile-one journal publications and percentage of 4* outputs in Clinical Medicine, Physics and Psychology/Psychiatry/Neuroscience UoAs, and no relationship was found in the Classics and Anthropology/Development Studies UoAs, due to the fact that most publications in the latter two disciplines are not journal articles. Practical implications The findings provide an indication of the monetary value of a research output, from the perspectives of government funding for research, and also what makes a good output, i.e. whether a relationship exists between good quality output and the source of its publication. The findings may also influence future REF submission strategies in HEIs and ascertain that the impact rating of the journals is not necessarily a reflection of the quality of research in every discipline, and this may have a significant influence on the future of scholarly communications in general. Originality According to the author’s knowledge, this is the first time an investigation has estimated the monetary value of a good research output

Sex differences in mathematics and reading achievement are inversely related: within- and across-nation assessment of 10 years of PISA data

We analyzed one decade of data collected by the Programme for International Student Assessment (PISA), including the mathematics and reading performance of nearly 1.5 million 15 year olds in 75 countries. Across nations, boys scored higher than girls in mathematics, but lower than girls in reading. The sex difference in reading was three times as large as in mathematics. There was considerable variation in the extent of the sex differences between nations. There are countries without a sex difference in mathematics performance, and in some countries girls scored higher than boys. Boys scored lower in reading in all nations in all four PISA assessments (2000, 2003, 2006, 2009). Contrary to several previous studies, we found no evidence that the sex differences were related to nations’ gender equality indicators. Further, paradoxically, sex differences in mathematics were consistently and strongly inversely correlated with sex differences in reading: Countries with a smaller sex difference in mathematics had a larger sex difference in reading and vice versa. We demonstrate that this was not merely a between-nation, but also a within-nation effect. This effect is related to relative changes in these sex differences across the performance continuum: We did not find a sex difference in mathematics among the lowest performing students, but this is where the sex difference in reading was largest. In contrast, the sex difference in mathematics was largest among the higher performing students, and this is where the sex difference in reading was smallest. The implication is that if policy makers decide that changes in these sex differences are desired, different approaches will be needed to achieve this for reading and mathematics. Interventions that focus on high-achieving girls in mathematics and on low achieving boys in reading are likely to yield the strongest educational benefits

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration

Family doctors' problems and motivating factors in management of depression

BACKGROUND: Depression is a frequent psychiatric disorder, and depressive patient may be more problematic for the family doctors (FD) than a patient suffering from a somatic disease. Treatment of patients with depressive disorders is a relatively new task for Estonian FDs. The aim of our study was to find out the family doctors' attitudes to depression related problems, their readiness, motivating factors and problems in the treatment of depressive patients as well as the existence of relevant knowledge. METHODS: In 2002, altogether 500 FDs in Estonia were invited to take part in a tailor-made questionnaire survey, of which 205 agreed to participate. RESULTS: Of the respondents 185(90%) considered management of depressive patients and their treatment to be the task of FDs. One hundred and eighty FDs (88%) were themselves ready to deal with depressed patients, and 200(98%) of them actually treated such patients. Commitment to the interests of the patients, better cooperation with successfully treated patients, the patients' higher confidence in FDs and disappearance of somatic complaints during the treatment of depression were the motivating factors for FDs. FDs listed several important problems interfering with their work with depressive patients: limited time for one patient, patients' attitudes towards the diagnosis of depression, doctors' difficulties to change the underlying causes of depression, discontinuation of the treatment due to high expenses and length. Although 115(56%) respondents maintained that they had sufficient knowledge for diagnostics and treatment of depression, 181(88%) were of the opinion that they needed additional training. CONCLUSION: FDs are ready to manage patients who might suffer from depression and are motivated by good doctor-patient relationship. However, majority of them feel that they need additional training

Presynaptic Nicotinic α7 and Non-α7 Receptors Stimulate Endogenous GABA Release from Rat Hippocampal Synaptosomes through Two Mechanisms of Action

BACKGROUND: Although converging evidence has suggested that nicotinic acetylcholine receptors (nAChR) play a role in the modulation of GABA release in rat hippocampus, the specific involvement of different nAChR subtypes at presynaptic level is still a matter of debate. In the present work we investigated, using selective α7 and α4β2 nAChR agonists, the presence of different nAChR subtypes on hippocampal GABA nerve endings to assess to what extent and through which mechanisms they stimulate endogenous GABA release. METHODOLOGY/FINDINGS: All agonists elicited GABA overflow. Choline (Ch)-evoked GABA overflow was dependent to external Ca(2+), but unaltered in the presence of Cd(2+), tetrodotoxin (TTX), dihydro-β-erythroidine (DHβE) and 1-(4,4-Diphenyl-3-butenyl)-3-piperidinecarboxylic acid hydrochloride SKF 89976A. The effect of Ch was blocked by methyllycaconitine (MLA), α-bungarotoxin (α-BTX), dantrolene, thapsigargin and xestospongin C, suggesting that GABA release might be triggered by Ca(2+) entry into synaptosomes through the α7 nAChR channel with the involvement of calcium from intracellular stores. Additionally, 5-Iodo-A-85380 dihydrochloride (5IA85380) elicited GABA overflow, which was Ca(2+) dependent, blocked by Cd(2+), and significantly inhibited by TTX and DHβE, but unaffected by MLA, SKF 89976A, thapsigargin and xestospongin C and dantrolene. These findings confirm the involvement of α4β2 nAChR in 5IA85380-induced GABA release that seems to occur following membrane depolarization and opening calcium channels. CONCLUSIONS/SIGNIFICANCE: Rat hippocampal synaptosomes possess both α7 and α4β2 nAChR subtypes, which can modulate GABA release via two distinct mechanisms of action. The finding that GABA release evoked by the mixture of sub-maximal concentration of 5IA85380 plus sub-threshold concentrations of Ch was significantly larger than that elicited by the sum of the effects of the two agonists is compatible with the possibility that they coexist on the same nerve terminals. These findings would provide the basis for possible selective pharmacological strategies to treat neuronal disorders that involve the dysfunction of hippocampal cholinergic system

FADS2 Function Loss at the Cancer Hotspot 11q13 Locus Diverts Lipid Signaling Precursor Synthesis to Unusual Eicosanoid Fatty Acids

Background: Genes coding for the fatty acid desaturases (FADS1, 2, 3) localized at the cancer genomic hotspot 11q13 locus are required for the biosynthesis of 20 carbon polyunsaturated fatty acids (PUFA) that are direct eicosanoid precursors. In several cancer cell lines, FADS2 encoded D6 and D8 desaturation is not functional. Methodology/Principal Findings: Analyzing MCF7 cell fatty acids with detailed structural mass spectrometry, we show that in the absence of FADS2 activity, the FADS1 product D5-desaturase operates to produce 5,11,14–20:3 and 5,11,14,17–20:4. These PUFA are missing the 8–9 double bond of the eicosanoid signaling precursors arachidonic acid (5,8,11,14–20:4) and eicosapentaenoic acid (5,8,11,14,17–20:5). Heterologous expression of FADS2 restores D6 and D8-desaturase activity and normal eicosanoid precursor synthesis. Conclusions/Significance: The loss of FADS2-encoded activities in cancer cells shuts down normal PUFA biosynthesis, deleting the endogenous supply of eicosanoid and downstream docosanoid precursors, and replacing them with unusual butylene-interrupted fatty acids. If recapitulated in vivo, the normal eicosanoid and docosanoid cell signaling milieu would be depleted and altered due to reduction and substitution of normal substrates with unusual substrates, with unpredictable consequences for cellular communication