Langerhans Cell Histiocytosis of the Temporal Bone with Otic Capsule Involvement.

INTRODUCTION: This study is conducted to demonstrate that destructive lesions of the otic capsule by Langerhans cell histiocytosis (LCH) causing both radiographic and audiologic findings can be completely reversed with adequate treatment. Retrospective case review and analysis of clinical and imaging data were obtained as part of the diagnosis and treatment of patients with LCH of the temporal bone. METHODS: With Institutional Review Board (IRB) approval, cases of LCH involving the temporal bone were searched for within the institutional databases. Criteria for inclusion was histologic diagnosis of LCH and pretreatment computed tomography (CT) demonstrating temporal bone and/or otic capsule involvement and posttreatment follow-up CT/magnetic resonance imaging (MRI) scans obtained at least 6 months after starting treatment. RESULTS: We report eight cases of LCH of the temporal bone with three demonstrating otic capsule involvement radiographically and/or clinically. Review of posttreatment imaging revealed all three patients had complete restoration of the bony labyrinthine architecture and near or complete restoration of their hearing. CONCLUSIONS: Though LCH of the temporal bone is a common site within the spectrum of the disease, involvement of the otic capsule remains rare. Here, we report the largest series of otic capsule involvement by LCH and investigate whether both architecture and hearing are recovered with appropriate treatment. Lastly, restoration of the bony architecture of the labyrinth suggests the mechanism of LCH is demineralization and not ablative.

Nutrient reference value: non-communicable disease endpoints--a conference report.

Nutrition is complex-and seemingly getting more complicated. Most consumers are familiar with "essential nutrients," e.g., vitamins and minerals, and more recently protein and important amino acids. These essential nutrients have nutrient reference values, referred to as dietary reference intakes (DRIs) developed by consensus committees of scientific experts convened by the Institute of Medicine of the National Academy of Sciences, Engineering, and Medicine and carried out by the Food and Nutrition Board. The DRIs comprise a set of four nutrient-based reverence values, the estimated average requirements, the recommended dietary allowances (RDAs), the adequate intakes and the tolerable upper intake levels for micronutrient intakes and an acceptable macronutrient distribution range for macronutrient intakes. From the RDA, the US Food and Drug Administration (FDA) derives a labeling value called the daily value (DV), which appears on the nutrition label of all foods for sale in the US. The DRI reports do not make recommendations about whether the DV labeling values can be set only for what have been defined to date as "essential nutrients." For example, the FDA set a labeling value for "dietary fiber" without having the DV. Nutrient reference values-requirements are set by Codex Alimentarius for essential nutrients, and regulatory bodies in many countries use these Codex values in setting national policy for recommended dietary intakes. However, the focus of this conference is not on essential nutrients, but on the "nonessential nutrients," also termed dietary bioactive components. They can be defined as "Constituents in foods or dietary supplements, other than those needed to meet basic human nutritional needs, which are responsible for changes in health status (Office of Disease Prevention and Health Promotion, Office of Public Health and Science, Department of Health and Human Services in Fed Regist 69:55821-55822, 2004)." Substantial and often persuasive scientific evidence does exist to confirm a relationship between the intake of a specific bioactive constituent and enhanced health conditions or reduced risk of a chronic disease. Further, research on the putative mechanisms of action of various classes of bioactives is supported by national and pan-national government agencies, and academic institutions, as well as functional food and dietary supplement manufacturers. Consumers are becoming educated and are seeking to purchase products containing bioactives, yet there is no evaluative process in place to let the public know how strong the science is behind the benefits or the quantitative amounts needed to achieve these beneficial health effects or to avoid exceeding the upper level (UL). When one lacks an essential nutrient, overt deficiency with concomitant physiological determents and eventually death are expected. The absence of bioactive substances from the diet results in suboptimal health, e.g., poor cellular and/or physiological function, which is relative and not absolute. Regrettably at this time, there is no DRI process to evaluate bioactives, although a recent workshop convened by the National Institutes of Health (Options for Consideration of Chronic Disease Endpoints for Dietary Reference Intakes (DRIs); March 10-11, 2015; http://health.gov/dietaryguidelines/dri/ ) did explore the process to develop DVs for nutrients, the lack of which result in increased risk of chronic disease (non-communicable disease) endpoints. A final report is expected soon. This conference (CRN-International Scientific Symposium; "Nutrient Reference Value-Non-Communicable Disease (NRV-NCD) Endpoints," 20 November in Kronberg, Germany; http://www.crn-i.ch/2015symposium/ ) explores concepts related to the Codex NRV process, the public health opportunities in setting NRVs for bioactive constituents, and further research and details on the specific class of bioactives, n-3 long-chain polyunsaturated fatty acids (also termed omega-3 fatty acids) and their constituents, specifically docosahexaenoic acid and eicosapentaenoic acid.

Influence of carotene-rich vegetable meals on the prevalence of anaemia and iron deficiency in Filipino schoolchildren.

OBJECTIVE: To determine the effects of eating carotene-rich green and yellow vegetables on the prevalence of anaemia, iron deficiency and iron-deficiency anaemia in schoolchildren. SUBJECTS AND METHODS: Schoolchildren (n=104), aged 9-12 years, received standardized meals containing 4.2 mg of provitamin A carotenoids/day (mainly beta-carotene) from yellow and green leafy vegetables and at least 7 g dietary fat/day. The meals were provided three times/day, 5 days/week, for 9 weeks at school. Before and after the dietary intervention, total-body vitamin A pool size was assessed by using the deuterated-retinol-dilution method; serum retinol and beta-carotene concentrations were measured by high-performance liquid chromatography; and whole blood haemoglobin (Hb) and zinc protoporphyrin (ZnPP) concentrations were measured by using a photometer and a hematofluorometer, respectively. RESULTS: After 9 weeks, the mean total-body vitamin A pool size increased twofold (95% confidence interval (CI): -0.11, -0.07 micromol retinol; P<0.001), and serum beta-carotene concentration increased fivefold (95% CI: -0.97, -0.79 micromol/l; P<0.001). Blood Hb (95% CI: -1.02, -0.52 g per 100 ml; P<0.001) and ZnPP increased (95% CI: -11.82, -4.57 microol/mol haem; P<0.001). The prevalence of anaemia (Hb<11.5 g per 100 ml) decreased from 12.5 to 1.9% (P<0.001). There were no significant changes in the prevalence of iron deficiency or iron-deficiency anaemia. CONCLUSIONS: Ingestion of carotene-rich yellow and green leafy vegetables improves the total-body vitamin A pool size and Hb concentration, and decreases anaemia rates in Filipino schoolchildren, with no effect on iron deficiency or iron-deficiency anaemia rates.

Protective effect of total and supplemental vitamin C intake on the risk of hip fracture--a 17-year follow-up from the Framingham Osteoporosis Study.

UNLABELLED: Vitamin C may play a role in bone health. In the Framingham Study, subjects with higher total or supplemental vitamin C intake had fewer hip fractures and non-vertebral fractures as compared to subjects with lower intakes. Therefore, vitamin C may have a protective effect on bone health in older adults. INTRODUCTION: Dietary antioxidants such as vitamin C may play a role in bone health. We evaluated associations of vitamin C intake (total, dietary, and supplemental) with incident hip fracture and non-vertebral osteoporotic fracture, over a 15- to 17-year follow-up, in the Framingham Osteoporosis Study. METHODS: Three hundred and sixty-six men and 592 women (mean age 75 +/- 5 years) completed a food frequency questionnaire (FFQ) in 1988-1989 and were followed for non-vertebral fracture until 2003 and hip fracture until 2005. Tertiles of vitamin C intake were created from estimates obtained using the Willett FFQ, after adjusting for total energy (residual method). Hazard ratios were estimated using Cox-proportional hazards regression, adjusting for covariates. RESULTS: Over follow-up 100 hip fractures occurred. Subjects in the highest tertile of total vitamin C intake had significantly fewer hip fractures (P trend = 0.04) and non-vertebral fractures (P trend = 0.05) compared to subjects in the lowest tertile of intake. Subjects in the highest category of supplemental vitamin C intake had significantly fewer hip fractures (P trend = 0.02) and non-vertebral fractures (P trend = 0.07) compared to non-supplement users. Dietary vitamin C intake was not associated with fracture risk (all P > 0.22). CONCLUSION: These results suggest a possible protective effect of vitamin C on bone health in older adults.

Antioxidant status and biomarkers of oxidative stress in dogs with lymphoma.

BACKGROUND: Oxidative stress might play a role in carcinogenesis, as well as impacting morbidity and mortality of veterinary cancer patients. The purpose of this study was to evaluate antioxidant concentrations and biomarkers of oxidative stress in dogs with newly diagnosed lymphoma before treatment and once in remission, with comparison with healthy controls. HYPOTHESIS: Dogs with lymphoma have increased oxidant and reduced antioxidant concentrations compared with healthy controls, and that these abnormalities normalize once remission is achieved. ANIMALS: Seventeen dogs with lymphoma and 10 healthy controls. METHODS: Prospective, observational study. Measures of oxidative stress [malondialdehyde and total isoprostanes (isoP)] and antioxidants [alpha-tocopherol, gamma-tocopherol, oxygen radical absorbance capacity (ORAC), and glutathione peroxidase (GSHPx)] were assessed in dogs with newly diagnosed lymphoma before treatment compared with healthy control dogs. The same parameters were measured in the dogs with lymphoma on week 7 of the chemotherapy protocol when all dogs were in remission. RESULTS: At baseline, dogs with lymphoma had significantly lower alpha-tocopherol (P <.001) and gamma-tocopherol (P= .003) but higher GSHPx (P= .05), ORAC (P= .001), and isoP (P < .001) compared with healthy controls. In the dogs with lymphoma, alpha-tocopherol concentrations were higher (P= .005) and ascorbic acid were lower (P= .04) after treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that dogs with lymphoma have alterations in oxidant and antioxidant concentrations and that the status of some of these biomarkers normalize after remission. Further studies are warranted to determine whether antioxidant interventions to correct these are beneficial in the treatment of canine lymphoma.

Effects of consuming foods containing oat beta-glucan on blood pressure, carbohydrate metabolism and biomarkers of oxidative stress in men and women with elevated blood pressure.

OBJECTIVE: To assess the effects of consuming foods containing oat beta-glucan on blood pressure, carbohydrate homeostasis and biomarkers of oxidative stress. DESIGN: A randomized, double-blind, controlled clinical trial. SETTING: The trial was conducted at two clinics. SUBJECTS AND INTERVENTIONS: Ninety-seven men and women with resting systolic blood pressure 130-179 mm Hg and/or diastolic blood pressure 85-109 mm Hg were randomly assigned to consume foods containing oat beta-glucan or control foods for 12 weeks. Resting blood pressures, insulin and glucose values before and after standard breakfast meals, and four biomarkers of oxidative stress were measured before and at the end of the treatment period. RESULTS: Changes from baseline to week 12 in mean peak insulin and incremental area under the insulin curve differed significantly between groups (P=0.037 and 0.034, respectively), with the beta-glucan group showing declines and the control group remaining essentially unchanged. Blood pressure responses were not significantly different between groups overall. However, in subjects with body mass index above the median (31.5 kg/m(2)), both systolic (8.3 mm Hg, P=0.008) and diastolic (3.9 mm Hg, P=0.018) blood pressures were lowered in the beta-glucan group compared to controls. No significant differences in biomarkers of oxidative stress were observed between treatments. CONCLUSIONS: The results of the present trial suggest beneficial effects of foods containing beta-glucan from oats on carbohydrate metabolism, and on blood pressure in obese subjects.

Plasma antioxidants in subjects before hematopoietic stem cell transplantation.

UNLABELLED: Chemo-irradiation induced oxidative damage to vascular endothelium may contribute to pulmonary complications of hematopoietic stem cell transplantation (HSCT). We measured antioxidants, markers of oxidative stress and plasma antioxidant capacity in plasma or serum from 24 subjects at day 7 before HSCT and 20 control subjects. The plasma concentration of extracellular glutathione peroxidase (GPX-3) was significantly reduced in the HSCT subjects compared with controls (HSCT: 98+/-42 microg/ml, control: 169+/-56 microg/ml, P<0.0001). The concentration of gamma-tocopherol was significantly higher in the HSCT subjects compared with controls (HSCT: 207+/-103 microg/dl; CONTROL: 98+/-52 microg/dl; P=0.0002). The plasma concentrations of protein carbonyl, nitrotyrosine, malondialdehyde, alpha-tocopherol, vitamin A, homocysteine, cysteine and cysteinylglycine did not differ between HSCT and control subjects. Plasma from HSCT subjects was as effective as control plasma in quenching menadione-induced intracellular reactive oxygen species production in human microvascular endothelial cells. In summary, subjects before HSCT have significantly reduced plasma concentrations of GPX-3, elevated plasma gamma-tocopherol yet retains the ability to quench an acute oxidative stress. These changes may play a role in chronic oxidative stress in the HSCT population.

Mechanical stimulation promotes osteogenic differentiation of human bone marrow stromal cells on 3-D partially demineralized bone scaffolds in vitro.

Bone is a dynamic tissue that is able to sense and adapt to mechanical stimuli by modulating its mass, geometry, and structure. Bone marrow stromal cells (BMSCs) are known to play an integral part in bone formation by providing an osteoprogenitor cell source capable of differentiating into mature osteoblasts in response to mechanical stresses. Characteristics of the in vivo bone environment including the three dimensional (3-D) lacunocanalicular structure and extracellular matrix composition have previously been shown to play major roles in influencing mechanotransduction processes within bone cells. To more accurately model this phenomenon in vitro, we cultured human BMSCs on 3-D, partially demineralized bone scaffolds in the presence of four-point bending loads within a novel bioreactor. The effect of mechanical loading and dexamethasone concentration on BMSC osteogenic differentiation and mineralized matrix production was studied for 8 and 16 days of culture. Mechanical stimulation after 16 days with 10 nM dexamethasone promoted osteogenic differentiation of BMSCs by significantly elevating alkaline phosphatase activity as well as alkaline phosphatase and osteopontin transcript levels over static controls. Mineralized matrix production also increased under these culture conditions. Dexamethasone concentration had a dramatic effect on the ability of mechanical stimulation to modulate these phenotypic and genotypic responses. These results provide increased insight into the role of mechanical stimulation on osteogenic differentiation of human BMSCs in vitro and may lead to improved strategies in bone tissue engineering.

Role of vitamin E and oxidative stress in exercise.

Reactive oxygen species (ROS) play an important role as mediators of skeletal muscle damage and inflammation after strenuous exercise. These ROS arise largely from increases in mitochondrial oxygen consumption and electron transport flux. Bouts of intense exercise are associated with increases in lipid peroxidation, generating malondialdehyde and F(2alpha)-isoprostanes, and the release of muscle enzymes like lactate dehydrogenase and creatine kinase. Dietary and enzymatic antioxidant defenses appear to play a protective role in muscle cells by reducing associated oxidative damage to lipids, nucleic acids, and protein. However, studies of the use of dietary antioxidants like vitamin E to reduce exercise-induced muscle injury have met with mixed success. The equivocal nature of these results appear to reflect a diversity of factors including the antioxidant(s) tested, the nature and timing of the exercise, the age and fitness of the subjects, and the methodology for assessing oxidative stress.

Endothelin-1 induces phosphorylation of GATA-4 transcription factor in the HL-1 atrial-muscle cell line.

The transcription factor GATA-4 plays a central role in the regulation of cardiac-muscle gene transcription. The present study demonstrates that endothelin-1 (ET-1) induces GATA-4 activation and phosphorylation. The treatment of HL-1 adult mouse atrial-muscle cells with ET-1 (30 nM) caused a rapid increase in the DNA binding activity of GATA-4 within 3 min. The activation was associated with an upward mobility shift of the GATA-4 band on native PAGE in an electrophoretic- mobility-shift assay. The upward shift of the GATA-4 band also occurred on SDS/PAGE as monitored by immunoblotting. The in vitro treatment of nuclear extracts with lambda-protein phosphatase abolished the upward shift, indicating that GATA-4 was phosphorylated. ET-1 activated the p44/42 mitogen-activated protein kinase (MAPK) and the MAPK kinase (MEK) within 3 min, and PD98059 (a specific inhibitor of MEK) abolished the ET-1-induced GATA-4 phosphorylation. PMA also caused the rapid activation of MAPK and the phosphorylation of GATA-4. In contrast, the activation of MAPK by phenylephrine or H(2)O(2) was weak and did not lead to GATA-4 phosphorylation. Thus ET-1 induces a GATA-4 phosphorylation by activating a MEK-MAPK pathway.

Dynamic stabilization in 1sigma(u)-->1pi(g) excited nitrogen clusters.

High-resolution 1s near-edge spectra of molecular nitrogen and variable size nitrogen clusters obtained using monochromatic synchrotron radiation from the high brilliance BESSY-II storage ring facility are reported. The vibrationally resolved 1sigma(u)-->1pi(g) core-to-valence excitation band of clusters shows a distinct redshift of 6+/-1 meV relative to the isolated molecule, but the vibrational structure and linewidths are essentially unchanged. This shift is assigned to dynamic stabilization of 1sigma(u)-->1pi(g) excited molecules in clusters, arising from the dynamic dipole moment generated by core-hole localization in the low-symmetry cluster field. This leads to changes in intermolecular interactions compared to the ground-state cluster. Such spectral shifts are expected to occur generally in molecular clusters and in the corresponding condensed phase.

Elevated plasma F2-isoprostanes in patients on long-term hemodialysis.

BACKGROUND: End-stage renal disease (ESRD) patients on long-term hemodialysis (HD) may be under increased oxidative stress, caused by either HD or renal failure. Plasma F2-isoprostanes have been established as an important indicator of in vivo oxidative stress. METHODS: Plasma esterified F2-isoprostanes were measured in 25 HD patients and 23 controls with normal renal function, employing gas chromatography-mass spectrometry with negative chemical ionization (GC-MS-NCI). C-reactive protein (CRP) was determined concurrently in patients and controls by enzyme-linked immunosorbent assay (ELISA). alpha-Tocopherol, retinol, albumin and creatinine were also determined. RESULTS: The average total esterified F2-isoprostanes in the ESRD patients was 1.62 +/- 0.73 vs. 0.27 +/- 0.10 ng/mL in controls (P < 0.001), with no overlap between patients and controls. Plasma F2-isoprostanes in diabetic ESRD patients were similar to F2-isoprostanes in patients with other causes for renal failure. In a subset of 10 of these ESRD patients evaluated eight months after the initial measurement, plasma-esterified F2-isoprostanes were not altered by an individual dialysis session. Average plasma CRP values were also higher in HD patients (P < 0.02), but some patients had CRP values that were similar to controls. In the HD patients, total plasma F2-isoprostanes and plasma CRP were correlated (r = 0.48, P = 0.015). Plasma alpha-tocopherol did not differ between patients and controls, but plasma retinol was higher in patients (3.15 +/- 1.71 micromol/L) than in controls (1.97 +/- 0.51 micromol/L, P < 0.05). CONCLUSIONS: These results are consistent with the hypothesis that oxidative stress in ESRD patients contributes to increased values of esterified plasma F2-isoprostanes, with concurrent increases in plasma CRP levels in some patients. Impaired clearance of esterified F2-isoprostanes may contribute to the elevated levels in renal failure. Plasma esterified F2-isoprostanes may be a useful indicator to evaluate effectiveness of interventions to decrease oxidative stress and associated inflammation.

Effects of thiol antioxidants on hepatocyte growth factor signaling in cardiac myocytes.

We describe here novel antioxidant-sensitive events in which activation kinetics are delayed, leading to inhibition of cell signaling. Hepatocyte growth factor (HGF) transiently phosphorylated p44/42 mitogen-activated protein kinase (MAPK) with a peak at 3-5 min in HL-1 adult cardiac myocytes. Pretreatment of cells with thiol antioxidants, N-acetylcysteine or alpha-lipoic acid attenuated MAPK phosphorylation induced by a 3-min incubation with HGF. However, kinetic analysis revealed that the apparent inhibition of HGF signaling was due to a delay in the activation because HGF phosphorylated MAPK with a peak at 5-7 min in cells treated with thiol antioxidants. This 2-min delay in HGF activation of MAPK resulted in >5-min delay in phosphorylation of MAPK targets such as p90RSK and GATA-4. Hydrogen peroxide did not mimic HGF signaling, and HGF did not induce reactive oxygen species production. Thus, in cardiac myocytes, thiol antioxidants delay HGF-mediated MAPK activation and suppress subsequent signaling eventsvia reactive oxygen species-independent mechanism.

Multivitamin/mineral supplementation improves plasma B-vitamin status and homocysteine concentration in healthy older adults consuming a folate-fortified diet.

Elevated homocysteine has been identified as an independent risk factor for cardiovascular and cerebrovascular disease. Although multivitamin use has been associated with low plasma homocysteine concentrations in several observational studies, no clinical trials have been conducted using multivitamin/mineral supplements to lower homocysteine. We determined whether a multivitamin/mineral supplement formulated at about 100% Daily Value will further lower homocysteine concentration and improve B-vitamin status in healthy older adults already consuming a diet fortified with folic acid. In this randomized, double-blind, placebo-controlled trial, 80 free-living men and women aged 50-87 y with total plasma homocysteine concentrations of > or =8 micromol/L received either a multivitamin/mineral supplement or placebo for 56 d while consuming their usual diet. After the 8-wk treatment, subjects taking the supplement had significantly higher B-vitamin status and lower homocysteine concentration than controls (P: < 0.01). Plasma folate, pyridoxal phosphate (PLP) and vitamin B-12 concentrations were increased 41.6, 36.5 and 13.8%, respectively, in the supplemented group, whereas no changes were observed in the placebo group. The mean homocysteine concentration decreased 9.6% in the supplemented group (P: < 0.001) and was unaffected in the placebo group. There were no significant changes in dietary intake during the intervention. Multivitamin/mineral supplementation can improve B-vitamin status and reduce plasma homocysteine concentration in older adults already consuming a folate-fortified diet.

The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors.

OBJECTIVE: Somatostatin analogs are the first-line drugs for controlling hormone-mediated symptoms of carcinoid tumors. Prospective and retrospective studies have suggested that somatostatin analogs also have antiproliferative activity. The octapeptide lanreotide is available in sustained-release form, obviating the need for daily injections. METHODS: A total of 46 patients were enrolled in this open, prospective, phase II trial. They received lanreotide 30 mg i.m. every 14 days for 6 months when they had symptomatic carcinoid tumors, and lanreotide 30 mg i.m. every 10 days if they had nonsymptomatic tumors. Nonsymptomatic tumors were progressive before the start of the study. Tumor size was assessed every 3 months by means of computed tomography. The assessment was centralized and was made by an external panel. RESULTS: In all, 30 patients had symptomatic neuroendocrine tumors and 16 had asymptomatic neuroendocrine tumors. Five patients in the group with symptomatic tumors and two in the group with nonsymptomatic tumors were considered not to be evaluable. The mean duration of treatment was 12 months in the group with symptomatic tumors and 13 months in the other group. Among the 39 evaluable patients, two objective responses were obtained, giving an objective response rate of 5% (one in the group with symptomatic tumors and one in the other group). Nineteen patients had no significant increase in their tumor size for a mean of 9.5 months. CONCLUSIONS: Lanreotide is safe and well tolerated in patients with carcinoid tumors. It seems to have both symptomatic and antitumoral effects in this setting.

Efficacy and tolerability of the long-acting somatostatin analog lanreotide in acromegaly. A 12-month multicenter study of 58 acromegalic patients. French Multicenter Study Group on Lanreotide in Acromegaly.

OBJECTIVE: To determine the effects of the new somatostatin analogue, lanreotide, in its prolonged released form (PR), in patients with acromegaly. DESIGN: Prospective open multicenter non comparative study. SETTING: Thirty-three university-affiliated medical centers. PATIENTS: One hundred sixteen acromegalic patients with active disease, of whom 58 patients complied with the protocol and completed the 12-month period treatment. INTERVENTION: Lanreotide PR treatment was started at a dose of 30 mg intramuscularly every 14 days. If integrated mean plasma GH levels were not below 5 micrograms/L and/or IGF-I levels were not normalized after one month of treatment, injections were given every 10 days. The duration of the study was 12 months. RESULTS: After one month of treatment mean plasma GH and IGF-I levels had fallen from 10.7 +/- 11.1 micrograms/L (mean +/- SD; range, 2.6-74.8 micrograms/L; median, 7 micrograms/L) and 718 +/- 270 micrograms/L (range 338-1440 micrograms/L; median, 645 micrograms/L), respectively, to 7.8 +/- 10.1 micrograms/L and 575 +/- 252 micrograms/L, respectively. Thirty patients (22%) had plasma GH levels below 2.5 micrograms/L, and 8 patients (16%) had age-adjusted normal plasma IGF-I levels. At the sixth month of treatment mean plasma GH levels of 2.5 micrograms/L or less, and normal plasma IGF-I levels were observed in 33%, and 33% of patients, respectively. At the twelvth month of treatment, these percentages were 41%, and 41%, respectively. The interval between two injections was shortened (one injection every 10 days) in 8 of the 58 patients (13%) at the second month of treatment, and at the end of the study, 70% of patients required 3 injections per month. The most frequent adverse event elicited by enquiry was transient diarrhea (76% of patients), followed by abdominal pain (62%) and pain at the injection site (59%). Based on the analysis of a subgroup of 46 patients who had at least a measurement of fecal fat content after day 0 of the study, a non significant increase (from 4.2 +/- 3.4 to 5.1 +/- 4.3 g/24 h, p = 0.3) in mean steatorrhea was observed during treatment. Before treatment, steatorrhea was present in 9 (19%) patients. During the study, 15 additional patients (32%) developed persistent steatorrhea, and there was a transient increase in fecal fat content above 6 g/24 h in another 11 patients. After exclusion of the 7 patients (12%) with gallstones at enrollment, new gall-stones were diagnosed in 6 out of 50 patients (12%) during the study. CONCLUSION: Two or three monthly injections of lanreotide PR decreased GH concentration to less than 2.5 micrograms/L and normalized IGF-I levels in 41% of patients treated during 12 months. The good tolerability of this treatment, and the reduction in the frequency of injections, plus the sustained drug serum concentrations, confirm the usefulness of this new somatostatin analog formulation.

Relative reactivity of lysine and other peptide-bound amino acids to oxidation by hypochlorite.

Antibacterial and inflammatory responses of neutrophils and macrophages produce hypochlorite as a major oxidant. Numerous side chains of amino acids found in extracellular proteins can be modified by hypochlorite, including His, Arg, Tyr, Lys, Trp, and Met. We studied the relative reactivity of each of these amino acid residues in short N-blocked peptides, where other residues in the peptide were highly resistant to hypochlorite attack. Hypochlorite treatment led to modified peptides in each case, which were detected by changes in retention on reversed-phase HPLC. A distinct single product, consuming two equivalents of hypochlorite per equivalent of peptide, was obtained from the Lys-containing peptides. UV spectroscopy, nuclear magnetic resonance (NMR), and electrospray/mass spectroscopy identified this product as the dichloramine at the epsilon-amino group of the Lys side chain. The dichloramine at Lys did not decompose to form a detectable amount of carbonyl reactive with dinitrophenylhydrazine. The dichloramine at Lys did however quantitatively revert back to Lys during HCl digestion of the tetrapeptide for amino acid analysis, with simultaneous modification of the adjacent Phe residue. The formation of the dichloramine at Lys was not blocked by peptides or acetylated amino acids that contained Tyr, His, or Arg. In contrast, the presence of equimolar Met-containing peptide, or N-Acetyl-Trp, both inhibited the formation of the dichloramine at Lys. Thus, Met and Trp side chains of proteins might be able to protect Lys from chloramine formation under some circumstances, but this interpretation must consider that Met and Trp are typically found in relatively inaccessible hydrophobic sites, whereas lysine is typically exposed on the protein surface. The hierarchy of amino acid reactivities examined here will aid in the prediction of residues in biological samples most likely to be modified by hypochlorite.

The effects of a multivitamin/mineral supplement on micronutrient status, antioxidant capacity and cytokine production in healthy older adults consuming a fortified diet.

BACKGROUND: Inadequate micronutrient intake among older adults is common despite the increased prevalence of fortified/enriched foods in the American diet. Although many older adults take multivitamin supplements in an effort to compensate, studies examining the benefits of this behavior are absent. OBJECTIVE: To determine whether a daily multivitamin/mineral supplement can improve micronutrient status, plasma antioxidant capacity and cytokine production in healthy, free-living older adults already consuming a fortified diet. METHODS: An eight-week double-blind, placebo-controlled clinical trial among 80 adults aged 50 to 87 years (mean = 66.5 +/- 8.6 years). RESULTS: Multivitamin treatment significantly increased (p<0.01, compared to placebo) plasma concentrations of vitamins D (77 to 100 nmol/L), E (27 to 32 micromol/L), pyridoxal phosphate (55.1 to 75.2 nmol/L), folate (23 to 33 nmol/L), B12 (286 to 326 pmol/L)), C (55 to 71 micromol/L), and improved the riboflavin activity coefficient (1.23 to 1.15), but not vitamins A and thiamin. The multivitamin reduced the prevalence of suboptimal plasma levels of vitamins E (p=0.003), B12 (p=0.004), and C (p=0.08). Neither glutathione peroxidase activity nor antioxidant capacity (ORAC) were affected. No changes were observed in interleukin-2, -6 or -10 and prostaglandin E2, proxy measures of immune responses. CONCLUSIONS: Supplementation with a multivitamin formulated at about 100% Daily Value can decrease the prevalence of suboptimal vitamin status in older adults and improve their micronutrient status to levels associated with reduced risk for several chronic diseases.