Rex L. Jamison

Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals

BACKGROUND Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification. METHODS In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included 49,621 participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease [n=46,969] and three trials in patients with colorectal adenoma [n=2652]). All these trials were evenly randomised. The main outcome was incident cancer (ignoring non-melanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log-rank analyses to calculate the cancer incidence rate ratio (RR). FINDINGS During a weighted average scheduled treatment duration of 5·2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57·3 nmol/L for the folic acid groups vs 13·5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1·06, 95% CI 0·99–1·13, p=0·10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0·23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0·13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site. INTERPRETATION Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials. FUNDING British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards Agency.

Transport of sodium and urea in outer medullary descending vasa recta.

We dissected and perfused outer medullary vasa recta (OMVR) from vascular bundles in the rat. Permeabilities of sodium (PNa) and urea (Pu) were simultaneously determined from the lumen-to-bath efflux of 22Na and [14C]urea. PNa and Pu were also measured by in vivo microperfusion of descending (DVR) and ascending vasa recta (AVR) at the papillary tip of Munich-Wistar rats. In some OMVR PNa was indistinguishable from zero. The mean +/- SE of PNa (x 10(-5), cm/s) in OMVR was 76 +/- 9. Pu in OMVR was always very high (x 10(-5), cm/s), 360 +/- 14. There was no correlation between OMVR PNa and Pu. Inner medullary AVR and DVR had PNa of 115 +/- 10 and 75 +/- 10, respectively, and Pu of 121 +/- 10 and 76 +/- 11, respectively. PNa and Pu in papillary vasa recta were always nearly identical and highly correlated. Transport of [14C] urea in OMVR was reversibly inhibited by addition of unlabeled urea or phloretin to the bath and lumen, providing evidence for carrier-mediated transport. These data suggest that sodium and urea might traverse the wall of inner medullary vasa recta by a paracellular pathway while urea also crosses by a transcellular route in OMVR. Electron microscopic examination of seven in vitro perfused OMVR revealed no fenestrations and exposure of these vessels to 10 microM calcium ionophore A23187 or 1 nM angiotensin II resulted in reversible contraction, suggesting that in vitro perfused OMVR are DVR only.

The urinary concentrating mechanism.

Disorders of the urinary concentrating mechanism vary widely in their clinical importance. At one extreme, they may simply represent an inconvenience to the patient who has to arise several times e...

The effect of urea infusion on the urinary concentrating mechanism in protein-depleted rats.

To explore the role of urea in the urinary concentrating mechanism, the contents of vasa recta, Henles descending limbs and collecting ducts were sampled by micropuncture of the renal papilla before and after infusion of urea in 10 protein-depleted rats. Eight protein-depleted rats not given urea were similarly studied as a control group. After urea administration, osmolality and the concentrations of urea and nonurea solute of urine from both exposed and contralateral kideny increased significantly. The osmolality and urea concentration of fluid from the end of Henles descending limb and vasa recta plasma and the tubule fluid-to-plasma inulin ratio in the end-descending limb all increased significantly after urea infusion. We interpret these observations to indicate that urea enhances urinary concentration by increasing the abstraction of water from the juxtamedullary nephron (presumably the descending limb), in agreement with the prediction of recent passive models of the urinary concentrating mechanism. However, the concentration of urea in fluid from the descending limb after urea infusion was high (261 plus or minus 31 mM) and the difference in solium concentration between descending limb fluid and vasa recta was small and statistically insignificant.

Effect of chronic potassium loading on potassium secretion by the pars recta or descending limb of the juxtamedullary nephron in the rat.

Recently we demonstrated potassium secretion by the pars recta or by the descending limb of the juxtamedullary nephron. The purpose of this present investigation is to study the effect of a chronic high-potassium intake on this phenomenon. Fractional reabsorption of water and sodium by the juxtamedullary proximal nephron was decreased when compared to that in normal hydropenic rats. There was a striking increase in the fraction of filtered potassium at the end of the juxtamedullary descending limb from 94+/11% to 180+/18%, which was principally a result of enhanced potassium secretion. When the concentration of potassium in the collecting tubule fluid of potassium-loaded rats was reduced after the administration of amiloride, a sharp fall was observed in the amount of potassium which reached the end of the descending limb (64+/8%). A direct correlation was observed between the fraction of filtered potassium at the descending limb and the potassium concentration in the final urine (P less than 0.001). The findings suggest that potassium, like urea, normally undergoes medullary recycling, which is enhanced by chronic potassium loading.

A micropuncture study of collecting tubule function in rats with hereditary diabetes insipidus

The reabsorption of water and solute by the papillary collecting duct was studied during water diuresis and vasopressin-induced antidiuresis in young rats with hereditary hypothalamic diabetes insipidus. The tip of the left renal papilla was exposed and fluid was obtained by micropuncture from loops of Henle and from collecting ducts at the papillary tip, and at an average of 1 mm proximal to the tip. In water diuresis the ratio of tubule fluid to plasma (TF/P) osmolality (osm) of loop fluid was 1.73 +/-0.058 (SE); of fluid from the proximal collecting duct, 0.63 +/-0.027; and from the tip, 0.55 +/-0.024; indicating a substantial osmotic pressure difference across the collecting duct epithelium. The fraction of filtered water reabsorbed (x 100) by the terminal collecting duct was 1.58% +/-0.32. In antidiuresis the TF/P osm of loop fluid was 2.65 +/-0.109; of fluid from the proximal collecting duct, 2.20 +/-0.093; and from the tip, 2.71 +/-0.111; indicating a marked decrease in the driving force for water reabsorption. The fraction of filtered water reabsorbed (x 100) by the terminal collecting duct was reduced to 0.58% +/-0.08, while the delivery of solute to the same segment was unchanged from that in water diuresis. The glomerular filtration rate (GFR) of the right kidney declined from 327 +/-24.4 mul/min in water diuresis to 274 +/-24.4 mul/min in antidiuresis (P < 0.005); similar results were obtained in a study comparing right and left GFRs in five additional rats. Thus, fractional reabsorption (and very likely the absolute volume) of water reabsorbed by the terminal collecting duct was less in antidiuresis than in water diuresis (mean difference, 1.01% +/-0.29, P < 0.005).

Direct determination of vasa recta blood flow in the rat renal papilla.

Blood flow in vasa recta capillaries of the exposed renal papilla of young antidiuretic rats (n = 18) was determined by an adaptation of the video-photometric technique of Intaglietta. The erythrocyte velocity and capillary diameter in vasa recta (« = 97) were measured at the same location by means of fluorescence video microscopy, with fluorescein-labeled bovine 7-globulin as a plasma marker. A factor relating erythrocyte velocity to mean cross-sectional blood velocity was determined in vitro to permit the calculation of single vasa recta blood flows from the measured indices, erythrocyte velocity and capillary diameter. Mean blood flow in descending vasa recta was 8.83 ± 0.96 (SE) nl/min, significantly greater than that in ascending vasa recta, 4.82 ± 0.34 nl/min. The total numbers of ascending and descending vasa recta at the base of the exposed papilla were also determined. Over 1500 vasa recta were identified as ascending vasa recta or descending vasa recta in electron micrographs of three papillas. At this level in the papilla (2 mm from the tip), there were four ascending vasa recta for each descending vas rectum. From the total numbers of ascending vasa recta and descending vas rectum, single vessel blood flows were converted to total blood flow. Total blood outflow in all ascending vasa recta, 11.3 μl/min, substantially exceeded total blood inflow in all descending vasa recta, 5.2 μmin. The difference between outflow and inflow (6.1 μ1/min) represents an estimate of water uptake by the papillary microcirculation, and is more than adequate to accommodate the known rate of water reabsorption from the collecting ducts of the exposed papilla.

Surreptitious diuretic ingestion and pseudo-Bartter's syndrome

A patient with profound hypokalemia satisfied the criteria for Bartters syndrome, including hyperreninemia, aldosteronism, normal blood pressure, and hyperplasia of the juxtaglomerular apparatus. Two screening tests of urine and one of plasma for diuretic agents gave negative results. A third urinary sample gave negative results for thiazide but positive for furosemide; the fourth and fifth samples gave negative results for furosemide but positive for thiazide. Urinary prostaglandin excretion was normal. We conclude that this apparent case of Bartters syndrome was caused by long term surreptitious diuretic ingestion and suggest this may occur more frequently than is generally appreciated.

The Natriuretic Peptides and Their Receptors

Atrial natriuretic factor (ANF) is released from the cardiac atrium in response to stretch and acts through receptors to cause an increase in urinary flow and sodium excretion, vasodilatation, and a reduction in blood volume. Recently, two new natriuretic peptides, brain natriuretic peptide (BNP) and C-type natriuretic peptide (C-typeNP), have been isolated, and three different natriuretic peptide receptors have been identified. Two of the receptors, ANP-RGC(A) and ANP-RGC(B), mediate biologic actions. The natural ligand of ANP-RGC(A) is ANF, whereas that of ANP-RGC(B) is C-typeNP. In view of clear differences in ligand specificity and tissue distribution of these receptors, it has been proposed that ANF and its receptor, ANP-RGC(A), and C-typeNP and its receptor, ANP-RGC(B), represent two distinct natriuretic peptide regulatory systems. Whether a separate system exists that incorporates BNP awaits clarification of its natural receptor that mediates a biologic action. The third receptor, ANP-Rc, binds all three natriuretic peptides. Its messenger RNA lacks the guanylyl cyclase sequence present in the mRNA of the other natriuretic peptide receptors, suggesting that the principal function of ANP-Rc is to remove natriuretic peptides from the circulation, that is, to regulate plasma levels of the natriuretic peptides. However, ANP-Rc may also mediate a biologic effect. These findings raise several intriguing questions about the functional role of this family of natriuretic peptides.

Effect of arginine vasopressin on renal medullary blood flow. A videomicroscopic study in the rat.

The role of arginine vasopressin (AVP) in the regulation of renal medullary blood flow is uncertain. To determine if AVP has a direct vasoconstrictive action on vasa recta, the effect of AVP on erythrocyte velocity (VRBC), diameter, and blood flow (QVR) in descending vasa recta (DVR) and ascending vasa recta (AVR) was studied in the exposed renal papilla of four groups of chronically water diuretic rats using fluorescence videomicroscopy. There were three periods: control (period 1), experimental (period 2), and recovery (period 3). In periods 1 and 3, all groups received hypotonic saline. In period 2, group I rats (AVP) received AVP (45 ng/h per kg body wt); group II (time) received hypotonic saline alone; group III (AVP plus V1-inhibitor) received AVP plus its vascular antagonist, d(CH2)5Tyr(Me)AVP; and group IV (V1-inhibitor) received the vascular antagonist alone. Another group of rats (group V) was employed to demonstrate that the rise in blood pressure induced by a 3- or 10-ng/kg injection of AVP was virtually abolished by the prior infusion of the V1-inhibitor. The urine of group III as well as group I rats was concentrated (Uosm = 721 +/- 62 H2O vs. 670 +/- 39 mosM/kg), while urine remained dilute in groups II and IV. In period 2, VRBC and QVR in DVR and AVR decreased in group I, did not decrease in group III, and increased in groups II and IV. The vascular antagonist thus completely abolished the AVP-induced decrease in QVR in group III. These findings unequivocally establish that AVP in physiological amounts reduces medullary blood flow, at least in part, by a direct vasoconstrictive action on the medullary microcirculation. They also show that an effect of AVP on medullary blood flow is not necessary for its antidiuretic effect.