Iron Is Filtered by the Kidney and Is Reabsorbed by the Proximal Tubule.

The aim of this study was to determine the iron (Fe) concentration profile within the lumen of the S2 renal proximal convoluted tubule (PCT) and to resolve whether this nephron segment transported Fe. To do this, we performed in vivo renal micropuncture on Wistar rats, collected PCT tubular fluid from superficial nephrons, and measured Fe concentration. The Fe concentration profile along the S2 PCT suggested significant Fe reabsorption. Proximal tubules were also microperfused in vivo with physiological solutions containing Fe and Zn, Cu, Mn, or Cd. PCTs perfused with 12µmol.l-1 55FeCl3 reabsorbed 105.2±12.7 fmol.mm-1.min-1 Fe, 435±52pmol.mm-1.min-1 Na, and 2.7±0.2nl.mm-1.min-1 water (mean ± SEM; n=19). Addition of ascorbate (1mmol.l-1) to the perfusate did not significantly alter Fe, Na, or water reabsorption. Supplementing the control perfusate with 60µmol.l-1 FeSO4 significantly decreased 55Fe uptake. Recalculating for the altered molar activity following addition of unlabeled Fe revealed a three-fold increase in Fe flux. Addition to the perfusate 12µmol.l-1 CuSO4, MnSO4, CdSO4, or ZnSO4 did not affect Fe, Na, or water flux. In conclusion, (1) in vivo, S2 PCTs of rat reabsorb Fe and (2) Fe is reabsorbed along the PCT via a pathway that is insensitive to Cu, Mn, Cd, or Zn. Together, these data demonstrate for the first time the hitherto speculated process of renal Fe filtration and subsequent tubular Fe reabsorption in a living mammal.

Beetroot juice lowers blood pressure and improves endothelial function in pregnant eNOS-/- mice: importance of nitrate-independent effects.

KEY POINTS: Maternal hypertension is associated with increased rates of pregnancy pathologies, including fetal growth restriction, due at least in part to reductions in nitric oxide (NO) bioavailability and associated vascular dysfunction. Dietary nitrate supplementation, from beetroot juice (BRJ), has been shown to increase NO bioavailability and improve cardiovascular function in both preclinical and clinical studies. This study is the first to investigate effects of dietary nitrate supplementation in a pregnant animal model. Importantly, the effects of nitrate-containing BRJ were compared with both 'placebo' (nitrate-depleted) BRJ as well as water to control for potential nitrate-independent effects. Our data show novel, nitrate-independent effects of BRJ to lower blood pressure and improve vascular function in endothelial nitric oxide synthase knockout (eNOS-/- ) mice. These findings suggest potential beneficial effects of BRJ supplementation in pregnancy, and emphasize the importance of accounting for nitrate-independent effects of BRJ in study design and interpretation. ABSTRACT: Maternal hypertension is associated with adverse pregnancy outcomes, including fetal growth restriction (FGR), due in part to reductions in nitric oxide (NO) bioavailability. We hypothesized that maternal dietary nitrate administration would increase NO bioavailability to reduce systolic blood pressure (SBP), improve vascular function and increase fetal growth in pregnant endothelial NO synthase knockout (eNOS-/- ) mice, which exhibit hypertension, endothelial dysfunction and FGR. Pregnant wildtype (WT) and eNOS-/- mice were supplemented with nitrate-containing beetroot juice (BRJ+) from gestational day (GD) 12.5. Control mice received an equivalent dose of nitrate-depleted BRJ (BRJ-) or normal drinking water. At GD17.5, maternal SBP was measured; at GD18.5, maternal nitrate/nitrite concentrations, uterine artery (UtA) blood flow and endothelial function were assessed, and pregnancy outcomes were determined. Plasma nitrate concentrations were increased in both WT and eNOS-/- mice supplemented with BRJ+ (P < 0.001), whereas nitrite concentrations were increased only in eNOS-/- mice (P < 0.001). BRJ- did not alter nitrate/nitrite concentrations. SBP was lowered and UtA endothelial function was enhanced in eNOS-/- mice supplemented with either BRJ+ or BRJ-, indicating nitrate-independent effects of BRJ. Improvements in endothelial function in eNOS-/- mice were abrogated in the presence of 25 mm KCl, implicating enhanced EDH signalling in BRJ- treated animals. At GD18.5, eNOS-/- fetuses were significantly smaller than WT animals (P < 0.001), but BRJ supplementation did not affect fetal weight. BRJ may be a beneficial intervention in pregnancies associated with hypertension, endothelial dysfunction and reduced NO bioavailability. Our data showing biological effects of non-nitrate components of BRJ have implications for both interpretation of previous findings and in the design of future clinical trials.

Melatonin Increases Fetal Weight in Wild-Type Mice but Not in Mouse Models of Fetal Growth Restriction.

Fetal growth restriction (FGR) presents with an increased risk of stillbirth and childhood and adulthood morbidity. Melatonin, a neurohormone and antioxidant, has been suggested as having therapeutic benefit in FGR. We tested the hypothesis that melatonin would increase fetal growth in two mouse models of FGR which together represent a spectrum of the placental phenotypes in this complication: namely the endothelial nitric oxide synthase knockout mouse (eNOS-/-) which presents with abnormal uteroplacental blood flow, and the placental specific Igf2 knockout mouse (P0+/-) which demonstrates aberrant placental morphology akin to human FGR. Melatonin (5 µg/ml) was administered via drinking water from embryonic day (E)12.5 in C57Bl/6J wild-type (WT), eNOS-/-, and P0+/- mice. Melatonin supplementation significantly increased fetal weight in WT, but not eNOS-/- or P0+/- mice at E18.5. Melatonin did, however, significantly increase abdominal circumference in P0+/- mice. Melatonin had no effect on placental weight in any group. Uterine arteries from eNOS-/- mice demonstrated aberrant function compared with WT but melatonin treatment did not affect uterine artery vascular reactivity in either of these genotypes. Umbilical arteries from melatonin treated P0+/- mice demonstrated increased relaxation in response to the nitric oxide donor SNP compared with control. The increased fetal weight in WT mice and abdominal circumference in P0+/-, together with the lack of any effect in eNOS-/-, suggest that the presence of eNOS is required for the growth promoting effects of melatonin. This study supports further work on the possibility of melatonin as a treatment for FGR.

Effects of dietary nitrate supplementation, from beetroot juice, on blood pressure in hypertensive pregnant women: A randomised, double-blind, placebo-controlled feasibility trial.

Chronic hypertension in pregnancy is associated with significant adverse pregnancy outcomes, increasing the risk of pre-eclampsia, fetal growth restriction and preterm birth. Dietary nitrate, abundant in green leafy vegetables and beetroot, is reduced in vivo to nitrite and subsequently nitric oxide, and has been demonstrated to lower blood pressure, improve vascular compliance and enhance blood flow in non-pregnant humans and animals. The primary aims of this study were to determine the acceptability and efficacy of dietary nitrate supplementation, in the form of beetroot juice, to lower blood pressure in hypertensive pregnant women. In this double-blind, placebo-controlled feasibility trial, 40 pregnant women received either daily nitrate supplementation (70 mL beetroot juice, n = 20) or placebo (70 mL nitrate-depleted beetroot juice, n = 20) for 8 days. Blood pressure, cardiovascular function and uteroplacental blood flow was assessed at baseline and following acute (3 h) and prolonged (8 days) supplementation. Plasma and salivary samples were collected for analysis of nitrate and nitrite concentrations and acceptability of this dietary intervention was assessed based on questionnaire feedback. Dietary nitrate significantly increased plasma and salivary nitrate/nitrite concentrations compared with placebo juice (p < 0.001), with marked variation between women. Compared with placebo, there was no overall reduction in blood pressure in the nitrate-treated group; however there was a highly significant correlation between changes in plasma nitrite concentrations and changes in diastolic blood pressure in the nitrate-treated arm only (r = -0.6481; p = 0.0042). Beetroot juice supplementation was an acceptable dietary intervention to 97% of women. This trial confirms acceptability and potential efficacy of dietary nitrate supplementation in pregnant women. Conversion of nitrate to nitrite critically involves oral bacterial nitrate reductase activities. We speculate that differences in efficacy of nitrate supplementation relate to differences in the oral microbiome, which will be investigated in future studies.

"Supporting nursing, midwifery and allied health professional students to raise concerns with the quality of care: A review of the research literature".

BACKGROUND: This article reports aspects of a systematic literature review commissioned by the UK Council of Deans of Health. The review collated and analysed UK and international literature on pre-registration healthcare students raising concerns with poor quality care. The research found in that review is summarised here. OBJECTIVE: To review research on healthcare students raising concerns with regard to the quality of practice published from 2009 to the present. DATA SOURCES: In addition to grey literature and Google Scholar a search was completed of the CINAHL, Medline, ERIC, BEI, ASSIA, PsychInfo, British Nursing Index, Education Research Complete databases. REVIEW METHOD: Sandelowski and Barroso's (2007) method of metasynthesis was used to screen and analyse the research literature. The review covered students from nursing, midwifery, health visiting, paramedic science, operating department practice, physiotherapy, chiropody, podiatry, speech and language therapy, orthoptist, occupational therapy, orthotist, prosthetist, radiography, dietitian, and music and art therapy. RESULTS: Twenty three research studies were analysed. Most of the research relates to nursing students with physiotherapy being the next most studied group. Students often express a desire to report concerns, but factors such as the potential negative impact on assessment of their practice hinders reporting. There was a lack of evidence on how, when and to whom students should report. The most commonly used research approach found utilised vignettes asking students to anticipate how they would report. CONCLUSIONS: Raising a concern with the quality of practice carries an emotional burden for the student as it may lead to sanctions from staff. Further research is required into the experiences of students to further understand the mechanisms that would enhance reporting and support them in the reporting process.

Dietary interventions for fetal growth restriction - therapeutic potential of dietary nitrate supplementation in pregnancy.

Fetal growth restriction (FGR) affects around 5% of pregnancies and is associated with significant short- and long-term adverse outcomes. A number of factors can increase the risk of FGR, one of which is poor maternal diet. In terms of pathology, both clinically and in many experimental models of FGR, impaired uteroplacental vascular function is implicated, leading to a reduction in the delivery of oxygen and nutrients to the developing fetus. Whilst mechanisms underpinning impaired uteroplacental vascular function are not fully understood, interventions aimed at enhancing nitric oxide (NO) bioavailability remain a key area of interest in obstetric research. In addition to endogenous NO production from the amino acid l-arginine, via nitric oxide synthase (NOS) enzymes, research in recent years has established that significant NO can be derived from dietary nitrate, via the 'alternative NO pathway'. Dietary nitrate, abundant in green leafy vegetables and beetroot, can increase NO bioactivity, conferring beneficial effects on cardiovascular function and blood flow. Given the beneficial effects of dietary nitrate supplementation to date in non-pregnant humans and animals, current investigations aim to assess the therapeutic potential of this approach in pregnancy to enhance NO bioactivity, improve uteroplacental vascular function and increase fetal growth.

Acute and chronic modulation of placental chorionic plate artery reactivity by reactive oxygen species.

Control of vascular resistance and blood flow in the fetoplacental circulation is incompletely understood. Reactive oxygen species (ROS), physiological and pathophysiological regulators of vascular tone, are elevated in preeclampsia (PE), a disease of pregnancy characterized by increased fetoplacental vascular resistance. We tested the hypothesis that ROS modulate vascular reactivity in placental chorionic plate arteries. Wire myography was used to examine (1) the effects of acute exposure to ROS on arterial function in normal pregnancy and (2) the effects of maternal antioxidant supplementation on arterial reactivity in women at high risk for PE participating in the Vitamins in Pre-eclampsia (VIP) trial. ROS generated by xanthine plus xanthine oxidase enhanced basal tension, vasoconstriction in response to the thromboxane mimetic U46619, and relaxation in response to sodium nitroprusside. Hydrogen peroxide and peroxynitrite increased basal tone and relaxed preconstricted arteries (U44619), respectively. In women at risk for PE, chorionic plate artery constriction in response to U46619 was greater in the women receiving placebo compared to the women supplemented with the antioxidant vitamins C and E. ROS may regulate fetoplacental vascular resistance and blood flow in the short term, and chronic exposure to raised ROS could contribute to elevated fetoplacental vascular resistance in PE and fetal growth restriction (FGR).

Reflective, holistic care after radical penectomy.

This case study describes the management of a patient with complex problems by a urology nurse specialist. Penile amputation and the creation of a colostomy had a severe impact on body image so the patient's care required a holistic approach. He also needed the support of community nurses, and collaboration between them and the urology nurse specialist prevented fragmentation of his care in the end stages of his life.