A Randomized, Placebo-Controlled, Pilot Clinical Trial to Evaluate the Effect of Supplementation with Prebiotic Synergy 1 on Iron Homeostasis in Children and Adolescents with Celiac Disease Treated with a Gluten-Free Diet.

Iron deficiency anemia (IDA) occurs in 15⁻46% of patients with celiac disease (CD), and in some cases, it may be its only manifestation. Studies in animal models have shown that prebiotics, including inulin, may help to increase intestinal absorption of iron. The aim of this study was to evaluate the effect of a prebiotic, oligofructose-enriched inulin (Synergy 1), on iron homeostasis in non-anemic children and adolescents with celiac disease (CD) in association with a gluten-free diet (GFD). Thirty-four CD patients (4⁻18 years old) were randomized into two groups receiving Synergy 1 (10 g/day) or a placebo (maltodextrin) for three months. Before and after intervention, blood samples were collected from all patients for assessment of blood morphology, biochemical parameters and serum hepcidin concentration. We found that serum hepcidin concentration after the intervention was significantly decreased by 60.9% (p = 0.046) in the Synergy 1 group, whereas no significant difference was observed in the placebo group. No differences in morphological and biochemical blood parameters (including ferritin, hemoglobin and C-reactive protein (CRP)) were observed after intervention in either group. Given that hepcidin decrease may improve intestinal iron absorption, these results warrant further investigation in a larger cohort and especially in patients with IDA.

Effects of Aerobic Exercise Combined with Panaxatriol Derived from Ginseng on Insulin Resistance and Skeletal Muscle Mass in Type 2 Diabetic Mice.

Insulin resistance reduces insulin-induced muscle protein synthesis and accelerates muscle protein degradation. Ginseng ingestion has been reported to improve insulin resistance through the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. We hypothesized that panaxatriol (PT) derived from ginseng in combination with aerobic exercise (EX) may further promote protein synthesis and suppress protein degradation, and subsequently maintain muscle mass through the amelioration of insulin resistance. KKAy insulin-resistant mice were divided into control, panaxatriol only (PT), exercise only (EX), and EX+PT groups. EX and EX+PT ran on the treadmill for 45 min at 15 m/min 5 d/wk for 6 wk. PT and EX+PT groups were fed a standard diet containing 0.2% PT for 6 wk. Homeostasis model assessment for insulin resistance (HOMA-R) values was significantly improved after exercise for 6 wk. Moreover, EX+PT mice showed improved HOMA-R as compared to EX mice. p70S6K phosphorylation after a 4 h fast was significantly higher in EX than in the non-exercise control, and it was higher in EX+PT mice than in EX mice. Atrogin1 mRNA expression was significantly lower in EX than in the non-exercise control, and was significantly lowered further by PT treatment. EX and EX+PT mice showed higher soleus muscle mass and cross-sectional area (CSA) of the soleus myofibers than control animals, with higher values noted for both parameters in EX+PT than in EX. These results suggest that aerobic exercise and PT ingestion may contribute to maintain skeletal muscle mass through the amelioration of insulin resistance.

Zinc-Excess Intake Causes the Deterioration of Renal Function Accompanied by an Elevation in Systemic Blood Pressure Primarily Through Superoxide Radical-Induced Oxidative Stress.

Using rats fed 22 g/d of a control diet containing 0.005% zinc (Zn) or 2 Zn-excess diets containing 0.05% or 0.2% Zn for 4 weeks, we examined the mechanisms involved in the deterioration of renal function induced by Zn-excess intake. An increase in Zn intake elevated mean blood pressure (BP) and reduced renal blood flow (RBF) and inulin clearance in a dose-dependent manner. This decline in inulin clearance may be derived from a fall in RBF. Administration of the nitric oxide (NO) synthase inhibitor, Nω-nitro-l-arginine methyl ester, markedly increased mean BP and significantly decreased RBF in the 3 groups of rats. Administration of the exogenous superoxide radical (OO-) scavenger, tempol, significantly decreased mean BP and substantially increased RBF in all groups of rats. These observations suggest that both an elevation in systemic BP and a reduction in RBF seen in the 2 Zn-excess diet groups result from a decrease in the action of the vasodilator, NO, through the formation of peroxynitrite based on the nonenzymatic reaction of NO and increased OO- Indeed, the activity of the endogenous OO- scavenger, copper/Zn-superoxide dismutase, was significantly reduced in the vessel wall of rats fed 2 Zn-excess diets versus a control diet. 8-Hydroxy-2'-deoxyguanosine formation caused by OO- generation was notably elevated in the kidneys of rats fed 2 Zn-excess diets relatively to rats fed a control diet. Thus, Zn-excess intake leads to the aggravation of renal function concomitantly with an increase in systemic BP predominantly through the oxidative stress caused by OO^.

[Relationship between glomerular filtration rate, uric acid, and parathyroid hormone in children]. / Relation entre débit de filtration glomérulaire, parathormone et acide urique chez l'enfant.

INTRODUCTION: Parathyroid hormone (PTH) and uric acid (UA) levels increase early during chronic kidney disease (CKD). The objective of this study was to evaluate the relationship between these two parameters at different stages of pediatric CKD. PATIENTS AND METHODS: One hundred patients (range, 5-18 years) were included in this retrospective study: they had undergone renal exploration with a direct measurement of the glomerular filtration rate (GFR) using the reference standard (i.e., inulin clearance, Cin) and presented with increased circulating levels of PTH and/or UA. RESULTS: GFR was normal in 39% of patients, with UA increased in 44% and PTH in 75% of them. Interestingly, 29% of the children with increased PTH levels had a strictly normal GFR (i.e., above 90 mL/min/1.73 m(2)). An inverse association was found between UA and GFR (r=-0.452, P ≤ 0.0001) as well as between PTH and GFR (r=-0.226, P=0.024). The same negative relationships were found between UA and PTH (r=-0.266, P=0.007), and between UA and the phosphate reabsorption rate (r=-0.415, P<0.001). DISCUSSION: Since hyperuricemia was found at all stages of CKD, an early silent tubular impairment can be discussed to explain these findings. The early increase in PTH levels during CKD has not been described by all authors, with North American studies describing rather late increased PTH levels during CKD. Prospective studies are required to confirm these data and evaluate the role of UA in the pathophysiology of the mineral disorders observed during CKD.

Dietary long-chain PUFA enhance acute repair of ischemia-injured intestine of suckling pigs.

Infant formula companies have been fortifying formulas with long-chain PUFA for 10 y. Long-chain PUFA are precursors of prostanoids, which stimulate recovery of intestinal barrier function. Supplementation of milk with PUFA increases the content of arachidonic acid (ARA) in enterocyte membranes; however, the effect of this enrichment on intestinal repair is not known. The objective of these experiments was to investigate the effect of supplemental ARA on intestinal barrier repair in ischemia-injured porcine ileum. One-day-old pigs (n = 24) were fed a milk-based formula for 10 d. Diets contained no PUFA (0% ARA), 0.5% ARA, 5% ARA, or 5% EPA of total fatty acids. Following dietary enrichment, ilea were subjected to in vivo ischemic injury by clamping the local mesenteric blood supply for 45 min. Following the ischemic period, control (nonischemic) and ischemic loops were mounted on Ussing chambers. Transepithelial electrical resistance (TER) was measured over a 240-min recovery period. Ischemia-injured ileum from piglets fed 5% ARA (61.0 ± 14%) exhibited enhanced recovery compared with 0% ARA (16 ± 14) and 0.5% ARA (22.1 ± 14)-fed pigs. Additionally, ischemia-injured ileum from 5% EPA (51.3 ± 14)-fed pigs had enhanced recovery compared with 0% ARA-fed pigs (P < 0.05). The enhanced TER recovery response observed with ischemia-injured 5% ARA supplementation was supported by a significant reduction in mucosal-to-serosal flux of (3)H-mannitol and (14)C-inulin compared with all other ischemia-injured dietary groups (P < 0.05). A histological evaluation of ischemic ilea from piglets fed the 5% ARA showed reduced histological lesions after ischemia compared with the other dietary groups (P < 0.05). These data demonstrate that feeding elevated levels of long-chain PUFA enhances acute recovery of ischemia-injured porcine ileum.

Hypoglycaemic effect of Calamintha officinalis Moench. in normal and streptozotocin-induced diabetic rats.

The purpose of this study was to investigate the effects of a water extract from the aerial parts of Calamintha officinalis Moench., after either a single dose or daily oral administration for 15 days, on plasma blood glucose concentrations and basal insulin levels in normal and streptozotocin-induced diabetic rats (STZ diabetic rats). The results clearly demonstrated the hypoglycaemic effect of this plant extract in both normal and STZ diabetic rats. In addition, no changes were observed in basal plasma insulin concentrations after treatment with this plant in normal or STZ diabetic rats, indicating that the underlying mechanism of the plant's pharmacological action seems to be independent of insulin secretion. We conclude that the aqueous C. officinalis extract exhibits a significant hypoglycaemic effect in normal and STZ diabetic rats without affecting basal plasma insulin concentrations, and supports, therefore, its traditional use by the Moroccan population.

Amino acid ingestion improves muscle protein synthesis in the young and elderly.

We recently demonstrated that muscle protein synthesis was stimulated to a similar extent in young and elderly subjects during a 3-h amino acid infusion. We sought to determine if a more practical bolus oral ingestion would also produce a similar response in young (34 +/- 4 yr) and elderly (67 +/- 2 yr) individuals. Arteriovenous blood samples and muscle biopsies were obtained during a primed (2.0 micromol/kg) constant infusion (0.05 micromol.kg(-1).min(-1)) of L-[ring-2H5]phenylalanine. Muscle protein kinetics and mixed muscle fractional synthetic rate (FSR) were calculated before and after the bolus ingestion of 15 g of essential amino acids (EAA) in young (n = 6) and elderly (n = 7) subjects. After EAA ingestion, the rate of increase in femoral artery phenylalanine concentration was slower in elderly subjects but remained elevated for a longer period. EAA ingestion increased FSR in both age groups by approximately 0.04%/h (P < 0.05). However, muscle intracellular (IC) phenylalanine concentration remained significantly higher in elderly subjects at the completion of the study (young: 115.6 +/- 5.4 nmol/ml; elderly: 150.2 +/- 19.4 nmol/ml). Correction for the free phenylalanine retained in the muscle IC pool resulted in similar net phenylalanine uptake values in the young and elderly. EAA ingestion increased plasma insulin levels in young (6.1 +/- 1.2 to 21.3 +/- 3.1 microIU/ml) but not in elderly subjects (3.0 +/- 0.6 to 4.3 +/- 0.4 microIU/ml). Despite differences in the time course of plasma phenylalanine kinetics and a greater residual IC phenylalanine concentration, amino acid supplementation acutely stimulated muscle protein synthesis in both young and elderly individuals.

[Effects of atorvastatin on ischemic acute renal failure in aging rats]. / Effetti della atorvastatina nell'insufficienza renale acuta ischemica del ratto anziano.

BACKGROUND: Aging (O) rats have a greater susceptibility to renal ischemia than young (Y) rats due to an endothelial dysfunction partially reversed by exogenous administration of L-Arginine. Since statins are able to increase nitric oxide (NO) production, aim of the study was to evaluate whether pre-treatment with atorvastatin (ATO, 10 mg/kg/day for 12 days), had positive effects on ischemic acute renal failure (ARF) of aging rats. METHODS: Renal clearance studies (inulin) were performed 24 hours after ischemia in 6 Groups (n=6 in each Group) of both Y- and O-rats: control rats (CON), untreated rats with ARF (Groups IRA), and rats with ARF but pretreated with ATO (Groups ATO+IRA). RESULTS: Renal ischemia determined a sharper decrease in GFR of Group O-IRA than Y-IRA (-80% and -63% vs respective CON, both p<0.001). In both Groups the fall in GFR was secondary to renal vasoconstriction and the consequent reduction in renal plasma flow. Pre-treatment with ATO did not modify GFR in Group Y-ATO+IRA, but was able to determine a marked rise in GFR of rats of O-ATO+IRA Group (+100% vs O-IRA), through a reduction in renal vascular resistances. Induction of ARF greatly enhanced nitrate excretion in Group Y-IRA, but slightly affected Group O-ARF. Administration of ATO did not modify nitrite excretion in Y rats, whereas it was able to increase nitrate excretion in O-ATO+ARF rats (+111% vs O-IRA). CONCLUSIONS: Pre-treatment with ATO is able to improve the renal response to ischemia in aging rats, through a mechanism which likely is NO-dependent.

Effect of amino acids and glucose on exercise-induced gut and skeletal muscle proteolysis in dogs.

The effect of amino acid and/or glucose administration before and during exercise on protein metabolism in visceral tissues and skeletal muscle was examined in mongrel dogs. The dogs were subjected to treadmill running (150 minutes at 10 km/h and 12% incline) and intravenously infused with a solution containing amino acids and glucose (AAG), amino acids (AA), glucose (G) or saline (S) in randomized order. The infusion was started 60 minutes before exercise and continued until the end of the exercise period. An arteriovenous-difference technique was used to estimate both tissue protein degradation and synthesis. When S was infused, the release of leucine (Leu) from the gut and phenylalanine (Phe) from the hindlimb significantly increased during exercise, thus indicating that exercise augmented proteolysis in these tissues. The balance of Leu across the gut during exercise demonstrated a net uptake with both AAG and AA, whereas a net release was observed for G and S. In addition, Leu uptake in the gut during the last 90 minutes of the exercise period tended to be greater with AAG versus AA (P = .06). Phe balance across the hindlimb during the late exercise period showed a significant release with S, AA, and G, whereas the balance with AAG did not show a significant release. These results suggest that exercise-induced proteolysis in the gut may be reduced by supplementation with AA, and this effect may be enhanced by concomitant G administration. However, in skeletal muscle, both AA and G may be required to prevent net protein degradation during exercise. G provided without AA did not achieve net protein synthesis in either tissue.

Diclofenac does not decrease renal blood flow or glomerular filtration in elderly patients undergoing orthopedic surgery.

UNLABELLED: Nonsteroidal antiinflammatory drugs (NSAIDs) have become increasingly popular in the treatment of perioperative pain. Due to concerns that cyclooxygenase inhibition may adversely affect renal function, these drugs are often not used in geriatric surgical patients. However, the perioperative effect of NSAIDs on renal blood flow (RBF) and glomerular filtration rate (GFR) has not been assessed. Therefore, using a prospective, controlled, double-blinded study design, we evaluated the effect of diclofenac on RBF and GFR in 20 patients (>65 yr) undergoing open reduction and internal fixation of the femur. All patients were normovolemic before the study. A standardized general anesthetic was administered. On induction of anesthesia, patients in the diclofenac group received an IV bolus of diclofenac (0.7 mg/kg) followed by a constant infusion (0.15 mg x kg(-1) x h(-1)) until the end of surgery. In the saline group, an equal volume of saline was administered. During four time periods (equilibration, anesthesia, surgical, recovery), GFR and effective renal plasma flow (ERPF) were measured by inulin and paraaminohippurate clearance, respectively. After the induction of anesthesia and throughout the surgical period, ERPF and GFR were significantly decreased compared with preoperative baseline values. However, no difference was demonstrated between the groups. These results suggest that, in geriatric surgical patients, the adjuvant administration of NSAIDs does not adversely affect renal function. IMPLICATIONS: As determined by inulin and paraaminohippurate clearance, the intraoperative administration of diclofenac does not decrease glomerular filtration rate or effective renal plasma flow in normovolemic geriatric patients. Therefore, diclofenac may be administered during the perioperative period.

A new method of measuring renal function in conscious rats without the use of radioisotopes.

The purpose of the current experiment was to develop fast and accurate assays for measuring glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). An enzymatic method was developed for the determination of inulin, and a colorimetric method was developed for determination of p-aminohippurate (PAH) in the plasma and urine of rats. These assays are easily automated and do not require the use of radioisotopes or corrosive chemicals. Glomerular filtration rate was measured by the clearance of inulin, and effective renal plasma flow was measured by the clearance of PAH. Blood pressure, heart rate, and renal function (urine volume, electrolytes, GFR, and ERPF) were measured in conscious rats for 1.5 h prior to drug treatment and for 3 h after treatment. Baseline renal function was compared to historical data. Acute changes in GFR and ERPF following administration of the vasoconstrictor peptide endothelin-1 (ET-1) were accurately measured with results similar to those obtained with older methodologies. These new methods offer many advantages over previously described methods by eliminating the use of radioisotopes and harsh chemicals. In addition, these methods can be used with an automated instrument with high accuracy and precision. Therefore, these new methods can be used to accurately determine GFR and ERPF and are sensitive enough to detect acute changes in GFR and ERPF in conscious animals.

The urinary concentrating defect in the Gunn strain of rat. Role of bilirubin.

The role of high serum and tissue levels of unconjegated bilirubin in the pathogenesis of the impaired urinary concentrating ability was investigated in homozygous (jj) Gunn rats with the congenital absence of hepatic glucuronyl transferase. Continuous phototherapy with blue fluorescent lights at a wave length of 460 nm or oral cholestyramine feeding or both reduced serum levels of unconjugated hilirubin to levels consistently below 3.0 mg/100 ml for several weeks in both weanling and adult jj Gunn rats. The renal concentrating defect was already present in weanling jj Gunn rats by 21 days of age. In treated weanling jj animals, maximum concentrating ability and the concentration of urea and nonurea solutes in the papilla and medulla, determined after 24 h of fluid deprivation, were normal when compared to unaffected heterozygous (Jj) littermates. Solute-free water reabsorption which is reduced in jaundiced jj Gunn rats was restored to normal in treated weanling jj rats. The tissue concentration of unconjugated bilirubin was reduced throughout the papilla and inner and outer medulla in the treated jj rats in comparison with untreated jj littermates. The defect in urinary concentrating ability was only partially reversible and sometimes irreversible in adult jj rats, probably because of permanent renal parenchymal damage occurring secondary to massive crystalline deposits in the papilla and medulla. It is concluded that unconjugated bilirubin is directly involved in the pathogenesis of the concentrating defect in jaundiced jj Gunn rats.