Search

Background: Evidence is mounting that price discounts can be effective in improving diet. This study examined the effectiveness of a 20% price discount on food and drink purchases with and without consumer education in remote Indigenous Australia. Methods: A 20% discount on fruit, vegetables, water, and artificially sweetened soft drinks was applied for 24 weeks in 20 communities in remote Indigenous Australia where the community store was managed by the Arnhem Land Progress Aboriginal Corporation (ALPA) or Outback Stores (OBS) in a stepped-wedge randomised trial. Communities were randomly allocated to a fixed framework of five sets of four stratified by store association; ten stores (two in each set) were randomly assigned to receive consumer education. A store from each of the ALPA and OBS store groups (contained in separate opaque envelopes) was selected, and stores in turn continued to be consecutively allocated to the fixed store set framework, starting with the first store slot in the first store set, until all stores had been allocated. The effect of the discount on the weight of fruit and vegetables purchased (the primary endpoint) was assessed using weekly store sales data and mixed models per protocol. We did sensitivity analyses by repeating the analyses with the outliers included and repeating the analyses for the primary outcome measure removing each store one at a time. This trial was registered with Australian New Zealand Clinical Trials Registry, number ACTRN12613000694718. Findings: Weekly store sales data on all food and drink products sold in 20 stores were collected from July 1, 2012, to Dec 28, 2014. Price discount alone was associated with a 12·7% (95% CI 4·1–22·1) increase in purchases in grams of fruit and vegetables combined (primary outcome), and a 19·8% (6·2–35·1) increase post discount (after vs before); an effect of 12 g and 18 g per capita per day. Sensitivity analyses did not modify the results for the primary outcome measure. Interpretation: A 20% discount can only increase fruit and vegetable purchases to help protect against obesity and diet related disease to a certain extent. Large discounts might have a greater impact than small discounts. Creative merchandising approaches to consumer education could also be considered alongside fiscal interventions to achieve marked improvements in diet. Funding: Australian National Health and Medical Research Council.

Diuretics are important drugs in the treatment of fluid overload and other related conditions in infants and children. Their rational use depends on adequate knowledge of how they work and how they interact with other drugs and the changing physiology caused by normal growth and development and by various disease states. It is in the best interest of the patient for the physician prescribing these drugs to have appropriate knowledge of their mode of action. It is clear that with the exception of a few drugs the amount of appropriate data available on the use of these drugs in children is limited at best. As newer drugs become available, the physician caring for such children must be sure that there is some clear indication for its use in preference to those with which we have more experience.

The kidney is a complex endocrine organ, and many of the renal hormones have actions that help regulate renal function. Although we have much more to learn about the role of most of these hormones in the regulation of renal function in both the newborn and adult kidney, there are some important aspects to keep in mind as we approach therapeutic interventions in sick newborn and premature infants. Because of the many interactions between hormonal systems, drugs that we may use for specific actions on one system may have effects on others as well (ACE inhibitors, cyclooxygenase inhibitors, dopamine antagonists). In addition, it is clear that the state of the organism may play a role in which of the renal hormones is active. Finally, the nonrenal hormonal systems that affect renal function (aldosterone, atrial natriuretic peptide, vasopressin, etc) may interact to change further expected results of any therapeutic intervention. Therefore, it behooves the clinician to monitor carefully renal function whenever modifications in therapy are made, whether it is a change in mechanical or pharmacologic intervention.

The pulmonary vasculature has been implicated in the clearance of several vasoactive substances from the circulation including angiotensin I (AI). In view of the previously reported age-related differences in angiotensin-converting enzyme (ACE) activity of lung homogenates, it was of interest to examine the ability of intact perfused lungs to metabolize AI. Lungs from newborn and adult rats were perfused with Krebs bicarbonate buffer containing 1.0 ng/ml AI in a single-pass, nonrecirculating system. The rate of perfusion was normalized to lung mass. Removal of AI was determined from the transpulmonary difference in radioimmunoassayable AI. Lungs from 7-day-old rats removed a smaller fraction of AI from the circulation than did adult lungs. The age-related increase in AI clearance was accompanied by an increase in pulmonary ACE content; however, enzyme content alone could not account for the observed differences. The increased metabolism of AI by the pulmonary vasculature during development may contribute to the age-related increase in circulating angiotensin II concentrations.

By using standard clearance and stop flow techniques, studies were carried out in anesthetized dogs to clarify further the mechanism(s) of excretion of renin in urine. The clearance of renin was 0.61 +/- 0.19 ml/min in control experiments and increased significantly to 1.26 +/- 0.38 ml/min after furosemide. The fractional excretion of renin increased from 1.51 +/- 0.45% during control to 3.90 +/- 0.98% after furosemide. The rate of excretion of renin was increased 10-fold during furosemide diuresis associated with a 10-fold increase in plasma renin concentration. Extracellular fluid volume expansion also produced a diuresis but no increase in plasma renin or renin excretion. Hemorrhage produced a 3.5-fold increase in plasma renin concentration and a 200-fold increase in urinary excretion of renin. When renal artery perfusion pressure was reduced to one kidney, the excretion of renin in the urine from that kidney increased, whereas there was no significant change in the excretion from the contralateral kidney. Reduction in renal artery perfusion pressure was associated with a 3-fold increase in the concentration of renin in the renal vein from the experimental kidney but an insignificant 2-fold increase in the arterial plasma renin concentration. Stop-flow studies demonstrated that renin enters the urine with the glomerular filtrate. The decreased concentration of renin in samples from the proximal tubule suggests that renin is being metabolized and/or reabsorbed in this nephron segment. In the distal nephron, there appears to be a site in which renin may be added to the tubular fluid. The results of these studies suggest that renin excretion in the urine is a complicated process. Excretion of renin in the urine is related in part to plasma renin activity but probably more importantly to the rate of production of renin in the kidney.

Asp1-125I-Tyr4-angiotensin II (125I-AII) was degraded during incubation with rat plasma or homogenates of liver or kidney. The electrophoretic profile of peptide fragments revealed that the disappearance of 125I-AII was first order and was accompanied by an accumulation of 125I-tyrosine in the incubation medium. The only other metabolites of angiotensin AII detectable by peptide mapping were the amino-terminus tetrapeptide and the carboxy-terminus hexapeptide. The appearance of these fragments was highly variable, suggesting that endopeptidases did not constitute the ultimate cleavage of angiotensin II hydrolysis. The half-life of 125-AII in plasma or liver homogenates did not change with age (approximately 8 to 12 and 6 to 9 min, respectively). In contrast, the rate of disappearance of 125I-AII in homogenates of rat kidney depended upon the age of the rat from which the tissue was obtained. The half-life of 125AII decreased three-fold (from approximately 8.3 to 2.8 min) between 2 wk after birth and adult (approximately 8 wk). This increase in the rate of metabolism of 125I-AII was accompanied by a concomitant two-fold, age-related increase in the rate of appearance of 125I-tyrosine in the reaction mixture containing renal tissue.

Experiments were performed on newborn piglets 6--96 hr of age. When the respiratory dead space was increased arterial pO2 decreased and pCO2 increased. During this time cardiac output was unchanged (Fig. 1), while heart rate, respiratory rate, and blood pressure increased (Figs. 2 and 3). After 90 min of asphyxia blood flow to the stomach and small and large intestines decreased. Changes in blood flow were associated with dilatation of segments of the small and large intestine with scattered areas of hemorrhage. Pathologic examination revealed scattered areas of mucosal necrosis (Fig. 6).

These experiments were designed to demonstrate that pretreatment of newborn dogs with penicillin will enhance maturation of the renal organic anion transport system in vivo. Littermate pups were injected with procaine penicillin G (300,000 I.U./kg b.i.d. for 3 days) or saline before 2 weeks of age. Animals were surgically prepared on day 16 or 17. Transport of p-aminhippurate (PAH), as an indicator of renal organic anion transport, was quantified by the following procedures: 1) disappearance of a bolus injection from the plasma, 2) renal extraction and 3) rate of secretion in steady-state clearance experiments. The renal handling of insulin was measured simultaneously in all procedures for comparison. Penicillin-treated animals excreted a single intravenous bolus of PAH more rapidly than control animals, with the T1/2 decreased and the constant of elimination (Ke) increased. The extraction of PAH by kidneys of penicillin-treated animals was 165% that of controls. Similarly, the tubular secretion of PAH was increased in treated pups. These data confirm that in newborn animals the renal handling of organic anions in vivo is enhanced by pretreatment with a substrate of the secretory system.

The effects of renal development on the response of newborns to acetazolamide were determined in an animal model, 5- and 20-day-old piglets. Increasing doses of acetazolamide increased both sodium and potassium excretion in 5-day-old piglets. Sodium excretion increased from 1.89 muEq/min during control periods to 15.7 muEq/min during infusion of acetazolamide (75 mg/kg/h). Potassium excretion increased to 20 muEq/min during acetazolamide infusion and urine pH increased from 5.7 to over 8.0. Sodium excretion by 20-day-old piglets given acetazolamide was similar to that of 5-day-old piglets but potassium excretion was twice as great (40 muEq/min). Changes in urine pH of the two groups were identical. It is concluded that the natriuretic response of 5-day-old piglets to acetazolamide is similar to that of older animals. In newborn piglets, moderate increases in sodium excretion by acetazolamide were accompanied by a marked kaliuresis. These data may identify a role for carbonic anhydrase in potassium excretion by newborn similar to that of adults.

The effects of furosemide on stimulation of renin secretion and urinary sodium excretion were studied in dogs pretreated with the prostaglandin synthetase inhibitors, indomethacin and meclofenamate. Pretreatment with these drugs failed to modify the natriuretic response to furosemide but completely blocked the rise in arterial plasma renin concentration produced by the diuretic. The organic acid probenecid did not affect either the natriuretic response or the increase in renin. In separate experiments, it was not possible to separate the effects of indomethacin on prostaglandin secretion, the renin-angiotensin system or renal hemodynamics. It is concluded that in the dog the natriuretic response to furosemide is not linked to the possible prostaglandin-induced increase in renal blood flow. Indomethacin apparently affects furosemide-induced renin secretion at both the vascular and macula densa sites. The data also suggest that the prostaglandins may be more important than the renin-angiotensin system in the modulation of intrarenal hemodynamics.

We studied the relative rates of release of active and inactive renin by the kidney in anesthetized pigs. Renin concentration was determined in arterial and renal venous plasma as follows: (1) before and after stimulation of renin release with isoproterenol or furosemide, (2) after suppression of renin release by extracellular fluid volume expansion, and (3) after administration of propranolol or indomethacin. Inactive renin was activated by dialysis of plasma at pH 3.3 for 24 hours. Renin concentration was estimated by radioimmunoassay determination of angiotensin I after a 3-hour incubation with excess homologous renin substrate. Following isoproterenol, the release of active renin increased from 8 +/- 4 (SEM) to 58 +/- 34 ng/min, and inactive renin increased from 53 +/- 33 to 321 +/- 136 ng/min. Similarly, furosemide stimulated the release of both active and inactive renin. Both forms of renin were suppressed by propranolol or indomethacin. Although changes in renin release following volume expansion were not statistically significant, the direction of change for both forms of renin was similar. Following logarithmic conversion of the rate of release, the plot of active vs. inactive renin formed a straight line. Values for active renin as a percentage of the total renin in simultaneously drawn arterial and renal venous plasma samples were not different. Thus, under the conditions of these experiments, release of active and inactive renin appears to be controlled by similar mechanisms. Both stimulation and suppression of renin release result in parallel changes in release of the two forms. Data on relative amounts of active renin in arterial and renal venous plasma suggest that there is no systemic conversion of the two forms.

The effect of inhibition of angiotensin I converting enzyme by captopril was studied in rats with aortic coarctation produced above the renal arteries. When captopril therapy was started before coarctation, blood pressure above the narrowing and the pressure difference across the coarctation were reduced, compared with values in animals with coarctation not given therapy. When captopril therapy was started 10 days after the coarctation, there was no effect on blood pressure. Plasma renin activity increased 24 hours after coarctation and returned to control levels by 5 days. Captopril caused an increase in renin activity and a decrease in plasma aldosterone concentrations. After 5 days, there was no difference in renin activity and plasma aldosterone levels between animals with coarctation given captopril therapy early and late and between appropriate controls. Our data suggest that the renin-angiotensin system is important in the early development but not in the maintenance of coarctation hypertension.

In view of the substrate-dependence of renin, it was of interest to examine the kinetics of the renin-angiotensinogen reaction in plasma of various species to establish differences in stoichiometry. The results also provide an indication of assay conditions appropriate for accurate measurement of the reaction velocity. Plasma from hogs, dogs, and rats served as the source of renin for incubation with homologous angiotensinogen. The rate of production of radioimmunoassayable angiotensin I increased with increasing concentrations of angiotensinogen. This substrate-dependence of renin conformed to conventional Michaelis-Menten kinetics. The concentration of angiotensinogen was less than that required for half maximum velocity in dog and rat plasma. In contrast, endogenous substrate in hog plasma was sufficient to sustain near maximal rates of generation of angiotensin I. Purification of angiotensinogen altered the catalytic properties of angiotensinogen making it a poor representative substrate for renin. Hog and rat renin were saturable with high concentrations of unextracted plasma angiotensinogen. In contrast, it was not possible to saturate the dog enzyme with unextracted substrate. The interspecies differences in stoichiometry of the reaction indicate that standardization of assay conditions for various species of renin is not justified.

The effects of furosemide, ethacrynic acid, hydrochlorothiazide and amiloride on renal function of newborn piglets, 5 to 10 days old, were evaluated. Furosemide and ethacrynic acid were the most effective diuretics. Furosemide infusion at 0.5 mg/kg/hr inhibited reabsorption of 21% filtered sodium and ethacrynic acid, 1 mg/kg/hr, increased fractional sodium excretion to 29%. Hydrochlorothiazide infusion produced a milder natriuresis than furosemide or ethacrynic acid. Infusion of hydrochlorothiazide at 1.0 mg/kg/hr increased fractional sodium excretion from 0.3% during the control period to 7.2%. Furosemide, ethacrynic acid and hydrochlorothiazide each increased potassium excretion to near 20 microEq/min. amiloride (1.0 mg/kg/hr) increased fractional sodium excretion from 0.2% during control period to 2.8% during drug infusion but did not affect potassium excretion. When infused in combination with furosemide and hydrochlorothiazide, amiloride increased the natriuresis and decreased the kaliuresis of both diuretics. It is concluded that the unanesthetized piglet is a good model for renal function of immature mammals and responds to diuretics in a manner qualitatively similar to adults.

Angiontensin-converting enzyme (ACE) catalyzes rapid conversion of angiotensin II (AII). This enzyme has been identified in the vascular endothelium of nearly every tissue. Inasmuch as AII is the biologically active component of the renin-angiotensin system, and since age-related differences exist in the renin-angiotensin system, it was of interest to determine converting enzyme activity during development. ACE activity was quantified by measuring the optical density of hippuric acid liberated from hippuryl-L-histidyl-L-leucine (HHL) following incubation with the 20,000 X g supernatant of tissue homogenates. Pulmonary ACE activity of near-term fetal rats was not different than 1-day-old animals. Therafter, ACE activity increased during the first 6 wk postpartum in a biphasic manner. A similar age-dependent increase in converting enzyme activity was observed in rat kidney, mouse kidney, and mouse lung. Substrate affinity of all enzymes measured was similar, suggesting that the age-related increase in activity was due to increased enzyme content. The low activity of ACE in the newborn might function to limit AII production.

The purpose of this investigation was to correlate the development of the various enzyme activities associated with the renin-angiotensin system with age-related differences in the steady-state concentrations of angiotensin I (AI) and II (AII). Angiotensin was quantified by radioimmunoassay. Plasma renin activity and concentration increased between birth and 3 wk of age, and declined thereafter to adult values. Renal renin content, on the other hand, increased throughout the first 6 wk of postnatal life. The concentration of AII in plasma also increased following birth; however, maximum concentrations were not attained until 5 wk of age. In contrast, plasma AI did not increase between 3 and 6 wk of age. These data suggest that the steady-state concentration of AII in neonatal rat plasma may be partially limited by the low plasma renin substrate concentration. The increase in AII between 3 and 6 wk of age may reflect the increasing converting enzyme activity.

This investigation was undertaken to determine the nature of acute alterations in renal function following the production of hypoxemia, hypercarbia, and acidosis in newborn piglets 6-96 hr of age. After completion of the surgical procedure piglets were allowed to recover from the effects of anesthesia. When respiratory dead space was increased arterial oxygen tension decreased whereas arterial carbon dioxide tension and hydrogen ion concentration increased. There was little change in glomerular filtration rate. Total renal blood flow decreased and renal vascular resistance increased significantly (504 +/- 78 mm Hg/liter/mm/m2 to 1422 +/- 504). There was no change in distribution of intrarenal blood flow. Sodium excretion and urinary flow rate demonstrated significant parallel increases following the increase in dead space. Plasma renin concentration increased from 67 to 110 ng/ml.

A case of nodular renal blastema developing into nephroblastomatosis is presented. Definitions and histopathology of these entities is given, and it is suggested that they represent a developmental spectrum with natural progression to Wilms' tumor.

The pulmonary vasculature has been implicated in the clearance of several vasoactive peptides, prostaglandins, and biogenic amines from the circulation. In view of the age-related differences in the metabolism of angiotensin by intact lungs, it was of interest to examine the maturation of 5-hydroxytryptamine (5-HT) disposition by isolated perfused lungs. Lungs from newborn and adult rats were perfused with Krebs bicarbonate buffer containing 0.1 microM 5-[14C]HT and samples of the effluent medium collected and analyzed for 5-HT and metabolite. Adult lungs removed and a greater fraction of perfused 5-HT than did lungs from 7-day-old rats. No age-related difference in monoamine oxidase (MAO) activity was observed; however, lung slices from adult rats incubated with 5-[14C]HT accumulated radiolabel at a greater rate than did slices from lungs of 7-day-old rats. The age-related difference in 5-HT clearance by intact lungs may be attributable to a relative deficiency in the facilitated transport process for 5-HT in newborns and may reflect a general functional maturation of processes associated with pulmonary endothelial cell membranes.

Angiotensin-converting enzyme (ACE) catalyzes rapid hydrolytic cleavage of angiotensin I to form angiotensin II (AII). Inasmuch as converting enzyme activity is present at birth and increases postnatally to adult values it was of interest to determine the prenatal development of ACE. Converting enzyme activity was determined in the 20,000 x g supernatant fraction of lung homogenates using hippuryl-L-histidyl-L-leucine (HHL) as substrate. Hippuric acid liberated by the hydrolysis of HHL was quantified spectrophotometrically. ACE activity was first detectable at 18 days of gestation and increased fourfold prior to birth (21 days gestation). Pulmonary ACE activity of 1-day-old animals was twice that of fetuses at day 20 of gestation; however, this increase did not appear to result from ventilation alone. The Michaelis-Menten constant for fetal ACE (2.0 mM HHL) was not different from that calculated for ACE of adult rat lungs (2.6 mM). These data were interpreted to indicate that the age-related increase in ACE activity was due to greater ACE content as opposed to further activation of preexisting enzyme. This increase in fetal ACE activity may play an important role in preparing the renin-angiotensin system for postnatal function.

The release of both active and acid-activatable (inactive), renin was determined in piglets ranging in age from 3 to 53 days. The concentration of active renin in arterial plasma during control periods decreased from 4.4 +/- 1.1 ng/ml in 3--5-day-old animals to 0.7 +/- 0.1 ng/ml in 42-53-day-old animals, while the rate of release of active renin was unchanged (11.8 +/- 5.1 ng/min and 7.5 +/- 3.4 ng/min, respectively). Both isoproterenol and furosemide stimulated release of renin in all age animals while propranolol supressed renin release. The data indicate that the qualitative control of renin release is similar in animals of various ages and stages of development. However, the differences in the concentration of renin in plasma of newborn and more mature animals may depend on factors other than release of renin by the kidney. Newborn animals release both active and inactive renin from the kidney.

Cytoplasmic microtubules appear to play a role in the secretion of a variety of protein and protein hormones. Involvement of microtubules in renin secretion has been hypothesized but not established. The present studies were designed to determine: 1) if the antimicrotubule drug, colchicine, would alter plasma renin concentration (PRC); and 2) if changes in PRC could be related to an effect on cytoplasmic microtubules. Dose response experiments in Sprague-Dawley rats showed that 0.4 or 0.8 mg/kg/day i.p. of colchicine for 3 days significantly increased PRC while a dose of 0.2 mg/kg/day was without effect. The increase in PRC at the higher doses was associated with toxicity of the drug. In other experiments, rats pretreated with colchicine (0.2 mg/kg/day) or saline received either furosemide (5 mg/kg) or isoproterenol (25 micrograms/rat) i.p. to stimulate renin secretion. Colchicine at a dose that did not alter basal PRC significantly inhibited an increase in PRC after stimulation with either isoproterenol or furosemide. Lumicolchicine, a structural isomer of colchicine without antimicrotubule activity, did not alter the response to isoproterenol stimulation. These data suggest that microtubules play a role in the increase in renin secretion following stimulation.

To investigate the influence of angiotensin II (AII) and renal prostaglandins on neonatal renal hemodynamics and sodium excretion, unanesthetized piglets 1-5, 18-20, and 45-50 days of age were treated with saralasin and indomethacin prior to volume expansion (VE) with isotonic saline. Saralasin did not affect basal renal blood flow (RBF) or the intrarenal distribution of blood flow as calculated as the ratio of outer-to-inner slice counts (O/I) in piglets 1-50 days of age. VE increased fractional sodium excretion equally in all animals. In 1- to 5-day-old piglets, saralasin blunted this natriuresis without affecting renal hemodynamics. Therefore, low neonatal RBF and O/I do not appear to be due to AII. In addition, indomethacin did not change renal hemodynamics in newborn piglets and did not affect the natriuresis after VE in any age group. Indomethacin decreased RBF and increased O/I of conscious 45- to 50-day-old animals. Renal prostaglandins do not appear to be a factor in control of renal hemodynamic in newborn pigs and do not influence the natriuresis in neonates following saline loading.

The effects of anesthetic agents, nitrous oxide-oxygen, nitrous oxide-oxygen plus ketamine, pentobarbital sodium and halothane, were determined in piglets 6 to 76 hr of age. After observations of cardiovascular and renal function in the unanesthetized state, the drugs were administered and observations were repeated in the anesthetized state. All of the anesthetics caused a decrease in cardiac output and an increase in total peripheral resistance in the newborn piglet. Both nitrous oxide-oxygen plus ketamine and halothane produced a decrease in heart rate while pentobarbital caused an increase and halothane a decrease in systemic blood pressure. Changes in renal function were minimal. Changes in renal blood flow were inconsistent and renal vascular resistance was not modified by any of the drugs. There was little evidence of redistribution of intrarenal blood flow and no significant changes in glomerular filtration rate or sodium excretion. Plasma renin concentration increased after halothane. It was concluded that changes in renal and cardiovascular function due to anesthesia in the newborn were small. Differences between newborn and adult animals may be related to several factors including the state of development of the autonomic nervous system and species differences used in different studies.