Rise In Serum Concentrations Research Articles

Impact of BMI on serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D with calcifediol supplementation in young adults: a longitudinal study.

High body mass index (BMI) is a risk factor for vitamin D deficiency. The rise in serum 25-hydroxyvitamin D [25(OH)D] concentrations following cholecalciferol supplementation is suboptimal, owing to adipose tissue sequestration and/or volumetric dilution. Calcifediol is a proven potent oral alternative for vitamin D supplementation, but whether BMI adversely affects its efficacy in raising 25(OH)D concentrations, is not well known. Adults with serum concentrations of 25(OH)D < 30 ng/mL were recruited and stratified as normal, overweight, or obese using WHO criteria. Baseline evaluation included 25(OH)D, parathyroid hormone (PTH), and total 1,25-dihydroxyvitamin D [1,25(OH)2D] based on BMI category (n = 883). A subset of participants was supplemented with 50 µg calcifediol (n = 193) and assessed for the rise in serum concentrations of 25(OH)D at 3- and 6-months following supplementation. Participants were stratified as obese (11.2%), overweight (32.1%), or normal weight (56.7%). There were no significant baseline differences in serum concentrations of 25(OH)D among the groups (13.1 ± 6.4 vs 12.8 ± 6.8 vs 11.6 ± 6.6 ng/mL, p = 0.62). Similarly, PTH or 1,25(OH)2D concentrations were not different among the groups. On follow-up, 25(OH)D concentrations increased in all three groups at 3 and 6 months from baseline. The increase in 25(OH)D was 74.4 ng/mL (IQR 35.3-115.3) in obese, followed by overweight 62.2 ng/mL (18.1-98.7) and normal weight groups 47.1 ng/mL (17.5-89.7) at 3 months. 1,25(OH)2D also increased in all groups, without any significant intergroup differences (p > 0.05). BMI does not impede the rise in 25(OH)D concentrations following supplementation with calcifediol in young adults with vitamin D deficiency.

Effects of Folic Acid Supplementation on Oxidative Stress Markers: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

(1) Background: This systematic review and meta-analysis aimed to assess the effects of folic acid supplementation on oxidative stress markers. (2) Methods: Online database including PubMed, Scopus, Web of Science, and Cochrane were searched up to January 2021, to retrieve randomized controlled trials (RCTs) which examined the effect of folic acid supplementation on markers of oxidative stress. Meta-analyses were carried out using a random-effects model. I2 index was used to evaluate the heterogeneity of RCTs. (3) Results: Among the initial 2322 studies that were identified from electronic databases search, 13 studies involving 1013 participants were eligible. Pooled effect size from 13 studies indicated that folic acid supplementation elicits a significant rise in serum concentrations of glutathione (GSH) (WMD: 219.01 umol/L, 95% CI 59.30 to 378.71, p = 0.007) and total antioxidant capacity (TAC) (WMD: 91.70 umol/L, 95% CI 40.52 to 142.88, p < 0.001) but has no effect on serum concentrations of nitric oxide (NO) (WMD: 2.61 umol/L, 95% CI −3.48 to 8.72, p = 0.400). In addition, folic acid supplementation significantly reduced serum concentrations of malondialdehyde (MDA) (WMD: −0.13 umol/L, 95% CI −0.24 to −0.02, p = 0.020). (4) Conclusions: This meta-analysis study suggests that folic acid supplementation may significantly improve markers within the antioxidative defense system by increasing serum concentrations of GSH and TAC and decreasing serum concentrations of MDA.

A randomized, controlled pilot study of the effects of vitamin D supplementation on balance in Parkinson's disease: Does age matter?

ObjectivesTo explore if short term, high dose vitamin D supplementation is safe and improves balance in persons with Parkinson's disease (PD).MethodsA pilot randomized, double-blind intervention trial to measure the effects of 16 weeks of high dose vitamin D (10,000 IU/day) on balance as well as other motor and non-motor features of PD. We measured balance, gait, strength, falls, cognition, mood, PD severity, and quality of life before and after 16 weeks of high dose vitamin D supplementation or placebo. All participants also received 1000 mg calcium once daily.ResultsFifty-one randomized participants completed sixteen weeks of high dose vitamin D supplementation or placebo. The intervention resulted in a rise in serum concentrations of vitamin D (25-OH) (30.2 ng/ml to 61.1 ng/ml) and was well tolerated with no serious adverse events. Serum vitamin D (25-OH) levels rose steadily and did not suggest a leveling off at the end of the 16 weeks. There was not an improvement in the primary endpoint, balance as measured by the Sensory Organization Test (p = 0.43). A post hoc analysis examining treatment effects in younger (ages 52–66) versus older (ages 67–86) participants found a significant improvement in the SOT of 10.6 points in the younger half of the cohort (p = 0.012).ConclusionsShort term, high dose vitamin D supplementation appears safe in persons with PD, but did not significantly improve balance as measured with the Sensory Organization Test in this pilot study population. A post hoc analysis suggests that vitamin D may have potential for improving balance in a younger population with PD. High dose vitamin D supplementation in PD needs further study especially in light of new research suggesting that mega doses and even moderate doses (as low as 4000IU a day) may increase falls in an older populations.Trial registrationClinicalTrials.gov: NCT01119131.

Activation and Inhibition of Transglutaminase 2 in Mice

Transglutaminase 2 (TG2) is an allosterically regulated enzyme with transamidating, deamidating and cell signaling activities. It is thought to catalyze sequence-specific deamidation of dietary gluten peptides in the small intestines of celiac disease patients. Because this modification has profound consequences for disease pathogenesis, there is considerable interest in the design of small molecule TG2 inhibitors. Although many classes of TG2 inhibitors have been reported, thus far an animal model for screening them to identify promising celiac drug candidates has remained elusive. Using intraperitoneal administration of the toll-like receptor 3 (TLR3) ligand, polyinosinic-polycytidylic acid (poly(I∶C)), we induced rapid TG2 activation in the mouse small intestine. Dose dependence was observed in the activation of TG2 as well as the associated villous atrophy, gross clinical response, and rise in serum concentration of the IL-15/IL-15R complex. TG2 activity was most pronounced in the upper small intestine. No evidence of TG2 activation was observed in the lung mucosa, nor were TLR7/8 ligands able to elicit an analogous response. Introduction of ERW1041E, a small molecule TG2 inhibitor, in this mouse model resulted in TG2 inhibition in the small intestine. TG2 inhibition had no effect on villous atrophy, suggesting that activation of this enzyme is a consequence, rather than a cause, of poly(I∶C) induced enteropathy. Consistent with this finding, administration of poly(I∶C) to TG2 knockout mice also induced villous atrophy. Our findings pave the way for pharmacological evaluation of small molecule TG2 inhibitors as drug candidates for celiac disease.

Generic antiepileptic drugs and increased health care utilization

The prescribing of generic antiepileptic drugs (AEDs) continues to generate much debate and much confusion.1–5 The fear is that seizures may recur with a fall in serum concentration or that toxicity may occur with a rise in serum concentration when the patient takes an AED from a different source. Such problems might arise when a branded drug is switched to a generic, when a generic is switched to a branded drug, or, indeed, when one generic is switched to another. These issues have been discussed extensively in the literature; the details of the arguments will not be repeated here. Worthwhile recommendations have been made. For example, the Italian League Against Epilepsy working group6 concluded that generic drugs meeting current regulatory criteria for bioequivalence represent a reasonable value choice in the management of epilepsy, particularly with patients for whom therapy is being initiated; they acknowledged, however, that a modest change in plasma drug levels could occur with drug substitution and this could, in rare cases, lead to seizure breakthrough. Generic substitution or changes between different generics were not recommended in patients who had achieved seizure remission. This recommendation does not account for those instances in which the choice of generic is not controlled by the physician or the patient. Labiner …

Serum concentration of lidocaine after transversus abdominis plane block

We measured the serum concentration of lidocaine after transversus abdominis plane (TAP) block with 40 ml of 1% lidocaine in 12 patients under general anesthesia, using a fluorescence polarization immunoassay. The peak mean serum concentration of lidocaine occurred 30 min after the block (3.6 +/- 0.7 microg x ml(-1)). The highest concentration of lidocaine (5.microg x ml(-1)) was recorded 15 min after the block. These results indicate that a TAP block can potentially cause systemic toxicity of a local anesthetic. The analgesic effect of the TAP block may partially depend on the rise in serum concentration of the local anesthetic.

Normal development and function of invariant natural killer T cells in mice with isoglobotrihexosylceramide (iGb3) deficiency

CD1d-restricted natural killer T (NKT) cells, expressing the invariant T cell antigen receptor (TCR) chain encoded by Valpha14-Jalpha18 gene segments in mice and Valpha24-Jalpha18 in humans [invariant NKT (iNKT) cells], contribute to immunoregulatory processes, such as tolerance, host defense, and tumor surveillance. iNKT cells are positively selected in the thymus by CD1d molecules expressed by CD4(+)/CD8(+) cortical thymocytes. However, the identity of the endogenous lipid(s) responsible for positive selection of iNKT cells remains unclear. One candidate lipid proposed to play a role in positive selection is isoglobotrihexosylceramide (iGb3). However, no direct evidence for its physiological role has been provided. Therefore, to directly investigate the role of iGb3 in iNKT cell selection, we have generated mice deficient in iGb3 synthase [iGb3S, also known as alpha1-3galactosyltransferase 2 (A3galt2)]. These mice developed, grew, and reproduced normally and exhibited no overt behavioral abnormalities. Consistent with the notion that iGb3 is synthesized only by iGb3S, lack of iGb3 in the dorsal root ganglia of iGb3S-deficient mice (iGb3S(-/-)), as compared with iGb3S(+/-) mice, was confirmed. iGb3S(-/-) mice showed normal numbers of iNKT cells in the thymus, spleen, and liver with selected TCR Vbeta chains identical to controls. Upon administration of alpha-galactosylceramide, activation of iNKT and dendritic cells was similar in iGb3S(-/-) and iGb3S(+/-) mice, as measured by up-regulation of CD69 as well as intracellular IL-4 and IFN-gamma in iNKT cells, up-regulation of CD86 on dendritic cells, and rise in serum concentrations of IL-4, IL-6, IL-10, IL-12p70, IFN-gamma, TNF-alpha, and Ccl2/MCP-1. Our results strongly suggest that iGb3 is unlikely to be an endogenous CD1d lipid ligand determining thymic iNKT selection.

Complexation of VEGF with bevacizumab decreases VEGF clearance in rats.

Angiogenesis plays a critical role in several physiologic and pathologic processes, particularly in tumor growth, invasion, and metastasis (1). New blood vessels provide tumors with nutrients necessary for growth and also remove metabolic waste from the tumor (2). Several growth factors have been implicated in tumor angiogenesis, and one such factor is vascular endothelial growth factor (VEGF), which is a selective mitogen for endothelial cells. VEGF, a 43to 46-kD glycoprotein, induces proliferation and migration of vascular endothelial cells and functions as a vascular permeability factor through two receptors: flt-1 and KDR (3). There are also several isoforms of VEGF (VEGF206, VEGF189, VEGF165, VEGF121, and VEGF110), and in humans, recombinant humanized VEGF165 (rhVEGF) displays nonlinear pharmacokinetics, which is attributed to binding of the drug to endothelial cells (4). In numerous preclinical animal models, administration of an antibody-targeting VEGF has been found to be a potent suppressor of tumor growth and is being considered as a potential, novel anticancer therapy (5). Bevacizumab (AvastinTM, rhuMAb VEGF) is a recombinant humanized monoclonal antibody that binds all isoforms of VEGF and inhibits binding of VEGF to its receptors. The antibody was engineered by combining VEGF-binding residues from a murine-neutralizing antibody with the framework of a human immunoglobulin G (IgG1) (6). Bevacizumab is believed to be cleared through the FcRn system, a MHC class I-related receptor that has been shown to protect circulating IgG1s from catabolism and thereby contribute to the long terminal half-life of antibodies (7). Bevacizumab binds to primate VEGF and to rabbit VEGF (with lower affinity) but does not bind to rodent VEGF (8). The monoclonal antibody has been shown to inhibit tumor growth in a dosedependent manner in various animal models (9). Several clinical studies have also been conducted to characterize the pharmacokinetics, safety, and efficacy of bevacizumab in cancer subjects. In two phase II studies in cancer subjects, bevacizumab, in combination with 5-fluorouracil/leucovorin or carboplatin/paclitaxel, has been shown to be safe and has inhibited tumor growth (10,11). Results from clinical studies have also shown a rise in serum concentrations of endogenous VEGF over baseline after single and multiple intravenous (IV) administration(s) of bevacizumab at doses >1 mg/kg (12). This rise in concentrations was ∼3to 4-fold above baseline and seemed to return to baseline as the antibody cleared systemically. An increase in VEGF synthesis/distribution and/or decrease in VEGF clearance upon complexation with bevacizumab are possible causes for this phenomenon. The latter hypothesis was explored in a pharmacokinetic study conducted in rats where recombinant humanized VEGF165 (rhVEGF) was administered intravenously in the presence or absence of bevacizumab. Rats were selected because (i) bevacizumab does not bind rat VEGF, therefore diminishing any competition for binding of bevacizumab to the administered rhVEGF and (ii) serial sampling was possible in the same animal for measurement of drug concentrations. Results presented here confirm that complexation of VEGF with bevacizumab decreases the clearance of circulating VEGF.

Historical Perspective of Turnover of Dominant Follicles During the Bovine Estrous Cycle: Key Concepts, Studies, Advancements, and Terms

This review chronicles the key concepts, studies, advancements and terms that have led to our current understanding of turnover of dominant follicles (growth and atresia) during the bovine estrous cycle. The “two-wave” concept of follicular development was first proposed in 1960, but remained controversial for the next 28 yr. The concept of the “dominant” follicle was adapted to cattle in 1987. By 1988, ultrasound analysis of individual follicles had demonstrated that heifers usually had two or three distinct waves of turnover of dominant follicles during an estrous cycle. From 1992 to 1993, it was established that a transient rise in serum concentrations of FSH initiated each follicular wave, and a decreased episodic secretion of LH was associated with loss of dominance and the end of a nonovulatory follicular wave. In the past decade, numerous intrafollicular growth factors, such as inhibins, activins, and insulin-like growth factors and their binding proteins, have been identified in follicular fluid of individual bovine follicles. In addition, in vitro studies demonstrate that these growth factors could have endocrine, autocrine, or paracrine actions that modify gonadotropin-stimulated follicular growth and differentiation. However, the precise role of intrafollicular growth factors in turnover of dominant follicles has not been defined. We concluded that two or three FSH-stimulated waves of follicular growth usually occur during the bovine estrous cycle, and each follicular wave culminates in development of a single nonovulatory or ovulatory dominant follicle.

PHEX expression in parathyroid gland and parathyroid hormone dysregulation in X-linked hypophosphatemia

X-linked hypophosphatemia (XLH), a renal phosphate (Pi) wasting disorder with defective bone mineralization, is caused by mutations in the PHEX gene (a Pi-regulating gene with homology to endopeptidases on the X chromosome). Parathyroid hormone (PTH) status in XLH has been controversial, with the prevailing belief that hyperparathyroidism develops in response to Pi therapy. We report a 5-year-old girl with XLH (patient 1) who had significant hyperparathyroidism at presentation, prior to initiation of therapy. We examined her response to a single oral Pi dose, in combination with calcitriol, and demonstrated a rise in serum concentration of intact PTH, which peaked at 4 h and paralleled the rise in serum Pi concentration. We also present two other patients whose parathyroid glands were analyzed for PHEX mRNA expression following parathyroidectomy. Patient 2 had autonomous hyperparathyroidism associated with chronic renal insufficiency, and patient 3, with XLH, developed autonomous hyperparathyroidism after 8 years of therapy with Pi and calcitriol. Following parathyroidectomy, patient 3 exhibited an increase in both serum Pi concentration and renal Pi reabsorption. The abundance of PHEX mRNA, relative to beta-actin mRNA, in parathyroid glands from patients 2 and 3 was several-fold greater than that in human fetal calvaria, as estimated by ribonuclease protection assay. In summary, we have shown that hyperparathyroidism can be a primary manifestation of XLH and that PHEX is abundantly expressed in the parathyroid gland. Given that PHEX has homology to endopeptidases, we propose that PHEX may have a role in the normal regulation of PTH.

RELEASE OF C1-INHIBITOR FROM PLATELET ALPHA GRANULES REGULATES COMPLEMENT ACTIVATION IN AN In Vitro MODEL OF VENTRICULAR ASSIST

Introduction: Ventricular Assist Devices (VAD) have improved the survival of patients with end-stage heart failure. However, long-term use of VADs are complicated by thromboembolism. Complement activation may play a role in these complications. Previous data has shown lower levels of complement activation in VADs treated with Aggrastat, a platelet GP IIb/IIIa inhibitor. Complement is regulated by the release of C1 esterase inhibitor (C1 INH) from platelet alpha granules by a receptor-mediated process. Platelet factor 4 (PF4) is a member of the chemokine superfamily of proinflammatory cytokines, which also resides in platelet alpha granules and can be used as a marker for platelet degranulation. The purpose of this study is to confirm that increases in serum concentrations of C1-INH, in response to VAD-induced complement activation, are caused by platelet degranulation in an in vitro VAD model. Methods: Eight in vitro non-pulsatile centrifugal VAD circuits were circulated for 4 days using 450 ml of fresh human whole blood. A highly selective inhibitor of platelet receptor GP IIb/IIIa (Aggrastat) was added to 4 of the circuits while the remaining 4 circuits were untreated. Temperature, ACT, cardiac index, pH, pCO (2), pO2, Ca++, and glucose were maintained at physiologic values. Serum levels of PF4 and C1-INH were measured by ELISA. Figure 1Figure 1Results: PF4 levels of VADs treated with Aggrastat increased to 389% of baseline levels by 72 hrs of VAD circulation while the untreated group increased by 569%. In untreated VADs, PF4 and C1-INH levels show an early rise in serum concentration that peaks at approximately hour 5 of circulation. Discussion: Treatment of in vitro VADs with Aggrastat reduced serum levels of PF4 suggesting that GP IIb/IIIa inhibition may attenuate the release of platelet alpha granule contents during degranulation. The early rise in both PF4 and C1-INH suggests that fluctuations in serum concentrations of C1-INH are attributed to platelet degranulation. Therefore, the early rise in CI-INH may be a regulatory response towards higher levels of complement activation in VADs without Aggrastat. Accordingly, lower levels of complement activation in VADs treated with Aggrastat may require less regulation causing a delayed rise of serum C1-INH. Figure 2Figure 2

Oral 4-aminosalicylic acid versus 5-aminosalicylic acid slow release tablets. Double blind, controlled pilot study in the maintenance treatment of Crohn's ileocolitis.

4-Aminosalicylic acid (4-ASA) has been suggested as an effective treatment for both active and quiescent ulcerative colitis. 5-Aminosalicylic acid (5-ASA) is well accepted for the maintenance treatment of inactive ulcerative colitis. Moreover, recent studies suggest that 5-ASA may also be effective in maintaining remission in Crohn's colitis. As treatment with 4-ASA may result in less side effects, the efficacy of a one year's maintenance treatment with oral 4-ASA (1.5 g/d, slow release tablets, n = 19) and oral 5-ASA (1.5 g/d, slow release tablets, n = 21) was compared in a double blind, randomised trial in patients with quiescent Crohn's ileocolitis. Patients with ileocolonic or colonic involvement were enrolled if in stable remission for more than two months but less than one year. Baseline demography and clinical severity were similar in both groups. Total colonoscopy and ileoscopy were performed at enrollment and at the end of the study. After one year seven of 19 patients receiving 4-ASA (36%) and 8 of 21 receiving 5-ASA (38%) had developed a clinical relapse, as defined by a rise in the Crohn's disease activity index (CDAI) of more than 100 points to values higher than 150. The relapse rates between the 4-ASA and the 5-ASA groups were not statistically different although no comparison with the spontaneous relapse rate in a placebo group could be made. Clinical relapse was accompanied by a statistically significant rise in serum concentrations of soluble interleukin 2 receptor and by an increased percentage of activated peripheral blood T cells. There were no statistical differences between the 4-ASA and the 5-ASA groups regarding the height of rise in CDAI or of soluble interleukin 2 receptor concentrations during relapse, thus showing a similar severity relapsed disease activity. In conclusion, 4-ASA maybe as effective as 5-ASA in the maintenance treatment of quiescent Crohn's disease and there were no differences in the severity of relapse between both treatment groups.

Oxcarbazepine

Oxcarbazepine is the 10-keto analogue of carbamazepine but has a distinct pharmacokinetic profile. In contrast to the oxidative metabolism of carbamazepine, oxcarbazepine is rapidly reduced to its active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine. With the possible exception of the P450IIIA isozyme of the cytochrome P450 family, neither oxcarbazepine nor its monohydroxy derivative induce hepatic oxidative metabolism. Direct comparison of oxcarbazepine and carbamazepine has shown no difference in efficacy between these 2 agents in terms of reducing seizure frequency in patients with partial epilepsy with or without secondary generalisation, or with tonic-clonic seizures. Substitution of oxcarbazepine for carbamazepine in multiple antiepileptic drug regimens improved seizure control in some patients with refractory epilepsy; however, the rise in serum concentrations of concurrent antiepileptic agents secondary to elimination of carbamazepine-associated hepatic enzyme induction may have also played a role. Substitution of oxcarbazepine for carbamazepine was associated with improved cognition and alertness in some patients with epilepsy. Limited data indicate that oxcarbazepine may be a useful alternative to carbamazepine in the management of trigeminal neuralgia. Experience in patients with acute mania is promising, but the value of oxcarbazepine in managing affective disorders, particularly as a prophylactic agent, is not established. Oxcarbazepine may be better tolerated than carbamazepine; however, the current published database is small and the potential for oxcarbazepine to induce the type of serious idiosyncratic reactions occasionally associated with carbamazepine is unknown. Hyponatraemia has been reported in patients treated with oxcarbazepine. Although apparently asymptomatic, fluid restriction may be deemed necessary in some patients to reduce the risk of precipitating seizures secondary to low serum sodium. Thus, oxcarbazepine appears to be an effective substitute for carbamazepine in those patients intolerant of this agent, or experiencing significant drug interactions. Wider clinical experience should help clarify the long term efficacy and tolerability of oxcarbazepine. Pharmacokinetic advantages over current antiepileptic drugs, carbamazepine in particular, may then favour oxcarbazepine for consideration as a first-line agent in the management of partial and tonic-clonic epilepsy.

Effect of late follicular phase administration of antide on ovulation and inhibin secretion in macaques

In previous studies, the LHRH antagonist detirelix, administered to stumptailed macaques during the menstrual cycle, was only partially effective in blocking pituitary-ovarian function when given during the late follicular phase. Since the antagonist was suppressive when administered during the early luteal phase, we investigated the ability of antide, a putative long-acting LHRH antagonist, to cause inhibition of the LH surge or luteal function when administered during the late follicular phase. Six animals with regular ovulatory cycles were treated on day 10 of the follicular phase with 1mg/kg antide s.c. All animals demonstrated a continued rise in serum concentrations of estradiol which were followed by an LH surge beginning 2–5 days after antide injection and serum progesterone and inhibin secretion which indicated normal luteal function. In a second experiment, six animals were treated on day 10 of the follicular phase with 3mg/kg antide s.c. In three animals, this caused a fall in serum concentrations of estradiol and the expected LH surge and rises in progesterone and inhibin secretion indicating ovulation failed to occur. In 2 animals,the LH surge was not prevented but the consequential rise in progesterone and inhibin was attenuated. In the remaining animal the cycle appeared unaffected. Pharmacokinetics of antide revealed an initial high release rate during the first 4 days (1mg/kg) or 6 days (3mg/kg) followed by a period of sustained release at a relatively low level. These results show that antide is partially effective in blocking ovulation at a high dose in the macaque and may result in an inadequate luteal phase, presumably as a result of its extended action.

Hyperaluminaemia in critically ill patients: role of antacid therapy and impaired renal function

A significant rise in serum concentrations of aluminum was demonstrated in 23 patients prophylactically treated with the antacid magaldrate, whereas no increase in serum aluminium was observed in another 26 critically ill patients, in whom the use of antacids was avoided. In parallel, urinary excretion rates of aluminum rose to values close to maximum 72 h after antacid therapy had been started. Hyperaluminaemia was most marked in patients with acute renal failure undergoing continuous haemofiltration, but a significant increment in serum aluminium was also noted in patients with impaired renal function in the predialytic state. In the latter group and in patients with normal renal function there was a significant negative correlation between urinary excretion rates of aluminium and creatinine clearance after 48 h of treatment suggesting an enhancement of gastrointestinal absorption of aluminium in the presence of chronic renal failure. Maximum serum concentrations of aluminium did attain critical values in some patients with acute renal failure, but no overt signs of aluminium toxicity were noted. However, in light of both, possible subtle toxicity and enhanced absorption of aluminium in critically ill patients with renal failure, the prophylactic use of antacids in this setting should be re-evaluated cautiously.

Effect of endothelin-1 in man.

The effect of an intravenous infusion of human endothelin-1 on blood pressure and plasma concentrations of endothelin-1, potassium, sodium, renin, aldosterone, and atrial natriuretic factor was investigated in six healthy, sodium-loaded men. During the peptide's exogenous application (1.0, 2.5, and 5.0 ng/kg.min), its plasma concentrations rose from a basal value of 1.2 +/- 0.3 to 3.2 +/- 1.9, 9.9 +/- 7.6, and 56.5 +/- 50.3 pmol/l (p less than 0.01), respectively, and mean blood pressure rose from a basal value of 87.1 +/- 7.3 to 92.6 +/- 8.2 mm Hg (p less than 0.01). A rise in serum concentrations of potassium (from 4.0 +/- 0.3 to 4.6 +/- 0.2 mmol/l; p less than 0.005) and a concomitant fall in serum concentrations of sodium (from 142.7 +/- 1.0 to 139.5 +/- 2.3 mmol/l; p less than 0.05) was seen in each subject. Plasma concentrations of renin, aldosterone, and atrial natriuretic factor did not change during the infusion of endothelin-1. Thus, in the doses used, endothelin-1 induces a rise in blood pressure and serum potassium concentrations.

Growth and reproductive performance of ewe lambs fed corn or soybean meal while grazing pasture.

In a 2-yr study a total of 120 Suffolk and Suffolk-cross ewe lambs, approximately 3 mo of age, were assigned within weight strata to one of three treatments: 1) control, pasture only (C), 2) .09 kg soybean meal/(hd.d) (SBM) plus pasture or 3) .45 kg whole shelled corn/(hd.) plus pasture to compare growth and reproductive performance and to determine lamb selectivity of forage quality and type. Each year, supplements were offered from June through the 3rd wk in November. Ewe lambs were managed as one flock on Kentucky bluegrass (Poa pratensis L.) and tall fescue (Festuca arundinacea Schreb.) pastures except for a brief daily supplementation period when all lambs were brought into a corral and sorted into treatment groups for the feeding. Ewe lambs were exposed to fertile rams from October 1 through the 3rd wk of November each year. Growth rates of ewe lambs grazing pasture alone were slower than those of corn-supplemented ewe lambs and were comparable to those of SBM-supplemented ewe lambs, but reproductive performances were similar (P greater than .05). Date of first detected rise in serum concentrations of progesterone and date of first observed estrus and lambing performance were similar (P greater than .05) among treatments for each year. Compared to hand-clipped forage, forage samples collected by esophageally fistulated lambs were higher (P less than .05) in crude protein and lower (P less than .05) in acid detergent fiber each year, indicating that lambs selectively grazed higher-quality forage. These data indicate that neither protein nor energy limited growth or reproductive performance of these ewe lambs.

Acute inhibition of somatotroph response to human growth hormone-releasing hormone 1–44 occurs following three hours but not one hour of growth hormone infusion

Our previous studies have demonstrated that a short-term (three hour) infusion of methionyl human growth hormone (met-hGH, 2 μg/kg/h) is associated with a rise in serum concentrations of free fatty acids and glycerol, and a blunting of somatotroph response to human growth hormone releasing hormone 1–44 (GRH) in normal volunteers. To gain more information on the time course of this blunting, and to determine whether it could be temporally dissociated from the GH-induced rise in serum concentrations of lipolytic products, the response to GRH (0.3 μg/kg) was measured in five normal adult volunteers from hours 1.0 to 3.5 of a 3.5-hour infusion of saline or met-hGH 2 μg/kg/h. Somatotroph response to the same dose of GRH from hours 3.0 to 5.5 of a longer (5.5-hour) infusion of saline or met-hGH (2 μg/kg/h) in five other volunteers was used for comparison. There was a significant blunting of somatotroph response following three hours, but not one hour of met-hGH infusion. The longer infusion was associated with a significant rise in serum concentrations of free fatty acids, and the shorter met-hGH infusion was too brief to provoke such a rise. Neither met-hGH infusion was associated with a significant rise in serum concentrations of glycerol, insulin, glucose, or insulin-like growth factors (IGF). This study provides further evidence that there is an association between circulating FFA and somatotroph function and suggests that FFA may act as messengers, which provide information to central systems regarding the energy balance of the organism.

A two-year follow-up study of serum insulinlike growth factor-I in diabetics with retinopathy

Serum insulinlike growth factor-I (IGF-I) concentration was evaluated prospectively over two years in 35 diabetic patients with severe background or preproliferative retinopathy (group 1) and 24 diabetics with mild background retinopathy matched for age, sex, and glycemic control (group 2). In addition, 12 normal subjects were also studied to assess the variability of individual serum IGF-I levels over two years. Mean serum IGF-I (±SD) μg/I at entry, one year, and two years was not significantly different in the patient groups (157 ± 71 v 168 ± 77; 166 ± 78 v 159 ± 87; 143 ± 58 v 159 ± 67) or when compared with the normal subjects (181 ± 47, 188 ± 30; 221 ± 56). Eight patients in the preproliferative group and none in the mild background group developed proliferative retinopathy. In this subgroup developing retinal neovascularization, serum IGF-I at the time of the first appearance of retinal new vessels was significantly higher than 3 months (1 to 4 months) before the onset of proliferation (271 ± 94 v 196 ± 58; P = .036). Values at the time of proliferation were not, however, significantly different from the mean serum IGF-I value of all patients in group 1 and by 4 months (3 to 6 m) had returned to their previous values. Although a transient elevation of IGF-I occurs at the time of retinal new vessel formation, the rise in serum concentration is not sufficiently great or early enough to be of clinical value as a predictor of retinal neovascularization.

Effects of Acute Intravenous Injection of Two Growth Hormone-Releasing Hormones (GHRH 1&amp;ndash;40 and 1&amp;ndash;29) on Serum Growth Hormone and Other Pituitary Hormones in Short Children with Pulsatile Growth Hormone Secretion

We administered two different growth hormone-releasing hormones (GHRH) to 20 short, prepubertal children who had spontaneous secretion of growth hormone (GH), assessed from 24-hour GH secretion profiles (72 sampling periods of 20 min). We compared one i.v. injection of 1 microgram/kg of GHRH 1-40 with that of GHRH 1-29 regarding serum concentrations of GH, prolactin, luteinizing hormone, follicle-stimulating hormone and IGF-I. The children were allocated to two groups without statistical randomization. Both groups were given both peptides, with at least 1 week in between. The first group started with GHRH 1-40, the other with GHRH 1-29. The peptides both induced an increased serum concentration of GH of the same magnitude: mean maximal peak of 89 +/- 12 mU/l after GHRH 1-40 and 94 +/- 10 mU/l after GHRH 1-29 (n.s.). The mean difference in maximum serum GH concentration in each child after injection was 52 +/- 9 mU/l, range 1-153 mU/l. GHRH 1-29 also induced a short-term, small increase in the concentrations of prolactin (p less than 0.05), luteinizing hormone (p less than 0.01) and follicle-stimulating hormone (p less than 0.05). We conclude that the shorter sequence GHRH 1-29, when given in a dose of 1 microgram/kg, gives a rise in serum concentration of GH similar to that after the native form GHRH 1-40.