Interpreting iron studies

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Seeing double: the low-carb diet

No abstract available

Systemic inflammation predicts all-cause mortality: a Glasgow Inflammation Outcome Study

Introduction: Markers of the systemic inflammatory response, including C-reactive protein and albumin (combined to form the modified Glasgow Prognostic Score), as well as neutrophil, lymphocyte and platelet counts have been shown to be prognostic of survival in patients with cancer. The aim of the present study was to examine the prognostic relationship between these markers of the systemic inflammatory response and all-cause, cancer, cardiovascular and cerebrovascular mortality in a large incidentally sampled cohort.<p></p> Methods: Patients (n = 160 481) who had an incidental blood sample taken between 2000 and 2008 were studied for the prognostic value of C-reactive protein (>10mg/l, albumin (>35mg/l), neutrophil (>7.5×109/l) lymphocyte and platelet counts. Also, patients (n = 52 091) sampled following the introduction of high sensitivity C-reactive protein (>3mg/l) measurements were studied. A combination of these markers, to make cumulative inflammation-based scores, were investigated.<p></p> Results: In all patients (n = 160 481) C-reactive protein (>10mg/l) (HR 2.71, p<0.001), albumin (>35mg/l) (HR 3.68, p<0.001) and neutrophil counts (HR 2.18, p<0.001) were independently predictive of all-cause mortality. These associations were also observed in cancer, cardiovascular and cerebrovascular mortality before and after the introduction of high sensitivity C-reactive protein measurements (>3mg/l) (n = 52 091). A combination of high sensitivity C-reactive protein (>3mg/l), albumin and neutrophil count predicted all-cause (HR 7.37, p<0.001, AUC 0.723), cancer (HR 9.32, p<0.001, AUC 0.731), cardiovascular (HR 4.03, p<0.001, AUC 0.650) and cerebrovascular (HR 3.10, p<0.001, AUC 0.623) mortality. Conclusion The results of the present study showed that an inflammation-based prognostic score, combining high sensitivity C-reactive protein, albumin and neutrophil count is prognostic of all-cause mortality

Hydrogenation and dehydrogenation with cyclometalated iridium (III) complexes

The selective hydrogenation and dehydrogenation of organic molecules is a fundamentally challenging and an attractive transformation for both, industry and academia. However, catalysts capable of undergoing both transformations under environmentally benign conditions are rare. In this thesis, our contribution to the development of a “universal” catalyst capable of achieving both hydrogenation and dehydrogenation of a wide range of organic compounds under mild conditions is presented. A general introduction covering the recent developments in the area of transfer hydrogenation of C=X (X = O, N) bonds, relevant applications of cyclometalated half-sandwich complexes and previous work in the area developed within our group is described in Chapter 1. In Chapter 2, Cyclometalated iridium complexes are shown to be highly efficient and chemoselective catalysts for the transfer hydrogenation of a wide range of carbonyl groups with formic acid in water. Examples include α-substituted ketones (α-ether, α-halo, α-hydroxy, α-amino, α-nitrile, α-ester), α-keto esters, β-keto esters, and α,β-unsaturated aldehydes. The reduction was carried out at substrate/catalyst ratios of up to 50000 at pH 4.5, requiring no organic solvent. The protocol provides a practical, easy and efficient way for the synthesis of β-functionalised secondary alcohols, such as β-hydroxyethers, β-hydroxyamines and β-hydroxyhalo compounds, which are valuable intermediates in pharmaceutical, fine chemical, perfume and agrochemical synthesis. In Chapter 3, the cyclometalated iridium complexes are shown to catalyse the transfer hydrogenation of various nitrogen heterocycles, including but not limited to quinolines, isoquinolines, indoles and pyridiniums, in aqueous solution under mild conditions. The catalyst shows excellent functional group compatibility and high turnover number (up to 7500), with loading as low as 0.01% being feasible. In Chapter 4, cyclometalated iridium complexes are found to be versatile catalysts for the direct reductive amination of carbonyls to give primary amines under transfer hydrogenation conditions with ammonium formate as both the nitrogen and hydrogen source. The activity and chemoselectivity of the catalyst towards primary amines is excellent, with a substrate to catalyst ratio of 1000 being feasible. Both aromatic and aliphatic primary amines were obtained in high yields. Moreover, a first example of a homogeneously catalysed transfer hydrogenative direct reductive amination (DRA) has been achieved for -keto ethers, leading to the corresponding -amino ethers. In addition, non-natural -amino acids could also be obtained in excellent yields with this method. Following the success of hydrogenation, cyclometalated iridium complexes were also found to be versatile catalysts for the oxidant-free, acceptorless dehydrogenation of various N-heterocycles, including tetrahydroquinolines, tetrahydroisoquinolines, tetrahydroquinoxalines and indolines. This protocol was also successfully applied to the total synthesis of alkaloids as presented in Chapter 5. Chapter 6 describes the development of a new strategy for the oxidant- and base-free dehydrogenative coupling of N-heterocycles at mild conditions. Under the action of an iridium cyclometalated catalyst, N-heterocycles undergo multiple sp3 C-H activation, generating a nucleophilic enamine that reacts in situ with various electrophiles to give highly functionalised products. The dehydrogenative coupling can be cascaded with Friedel-Crafts addition, resulting in double functionalisation of the N-heterocycles. The dehydrogenation products could also be saturated under either hydrogenation or transfer hydrogenation conditions, giving rise to structurally diverse products. Final conclusion and perspectives of the research covered in this PhD thesis are presented in Chapter 7

The effect of the systemic inflammatory response on plasma vitamin 25 (OH) D concentrations adjusted for albumin

<b>Aim</b><p></p> To examine the relationship between plasma 25(OH)D, CRP and albumin concentrations in two patient cohorts.<p></p> <b>Methods</b><p></p> 5327 patients referred for nutritional assessment and 117 patients with critical illness were examined. Plasma 25 (OH) D concentrations were measured using standard methods. Intra and between assay imprecision was <10%.<p></p> <b>Result</b><p></p> In the large cohort, plasma 25 (OH) D was significantly associated with CRP (rs = −0.113, p<0.001) and albumin (rs = 0.192, p<0.001). 3711 patients had CRP concentrations ≤10 mg/L; with decreasing albumin concentrations ≥35, 25–34 and <25 g/l, median concentrations of 25 (OH) D were significantly lower from 35 to 28 to 14 nmol/l (p<0.001). This decrease was significant when albumin concentrations were reduced between 25–34 g/L (p<0.001) and when albumin <25 g/L (p<0.001). 1271 patients had CRP concentrations between 11–80 mg/L; with decreasing albumin concentrations ≥35, 25–34 and <25 g/l, median concentrations of 25 (OH) D were significantly lower from 31 to 24 to 19 nmol/l (p<0.001). This decrease was significant when albumin concentration were 25–34 g/L (p<0.001) and when albumin <25 g/L (p<0.001). 345 patients had CRP concentrations >80 mg/L; with decreasing albumin concentrations ≥35, 25–34 and <25 g/l, median concentrations of 25 (OH) D were not significantly altered varying from 19 to 23 to 23 nmol/l. Similar relationships were also obtained in the cohort of patients with critical illness.<p></p> <b>Conclusion</b><p></p> Plasma concentrations of 25(OH) D were independently associated with both CRP and albumin and consistent with the systemic inflammatory response as a major confounding factor in determining vitamin D status.<p></p&gt

The role of thiamine dependent enzymes in obesity and obesity related chronic disease states: a systematic review

The WHO 2016 report indicates that worldwide obesity is rising, with over 600 million people in the obese range (BMI>30). The recommended daily calorie intake for adults is 2000 kcal and 2500 kcal for women and men respectively. The average American consumes 3770 kcal/day and the average person in the UK consumes 3400 kcal/day. With such increased caloric intake, there is an increased load on metabolic pathways, in particular glucose metabolism. Such metabolism requires micronutrients as enzyme co-factors. The recommended daily allowance (RDA) for thiamine is 1.3 mg/day and 0.5 mg thiamine is required to process 1000 kilocalories (kcal). Therefore, despite the appearance of being overfed, there is now increasing evidence that the obese population may nutritionally depleted of essential micronutrients. Thiamine deficiency has been reported to be in the region of 16-47% among patients undergoing bariatric surgery for obesity. Thiamine, in turn, requires magnesium to be in its active form thiamine diphosphate, (TDP). TDP also requires magnesium to achieve activation of TDP dependent enzymes, including transketolase (TK), pyruvate dehydrogenase (PDH) and alpha-keto glutaric acid dehydrogenase (AKGDH), during metabolism of glucose. Thiamine and magnesium therefore play a critical role in glucose metabolism and their deficiency may result in the accumulation of anaerobic metabolites including lactate due to a mismatch between caloric burden and function of thiamine dependent enzymes. It may therefore be postulated that thiamine and magnesium deficiency are under-recognized in obesity and may be important in the progress of obesity and obesity related chronic disease states. The aim of the present systematic review was to examine the role of thiamine dependent enzymes in obesity and obesity related chronic disease states

Erythrocyte concentrations of B1, B2, B6 but not plasma C and E are reliable indicators of nutrition status in the presence of systemic inflammation

Background & aim: There is increasing evidence that the plasma concentration of vitamin D, carotenoids, zinc and selenium are associated with the magnitude of the systemic inflammatory response. In order to examine whether other vitamins may be affected and whether red cell concentrations are less affected by systemic inflammation the aim of the present study was to examine the effect of the systemic inflammatory response on red cell measurements of vitamins B1, B2 and B6, and plasma concentration of vitamin C and E in a large cohort of patients referred for a nutritional screen. Methods: Patients referred for nutritional assessment of B1 (n = 551), B2 (n = 251), B6 (n = 313), ascorbic acid (n = 494) and α-tocopherol (n = 395) concentrations. These vitamins were measured using routine laboratory methods. Results: The median concentrations of vitamin B1 grouped according to C-reactive protein concentrations ≤10, 11–80 and >80 mg/L were 543, 664 and 766 ng/g Hb respectively (p < 0.001, 41% higher). The median concentration of vitamin B1 grouped according to albumin concentrations ≥35, 25–34 and <25 g/l were 547, 664 and 701 ng/g Hb respectively (p < 0.001, 28% higher). The median concentrations of red cell vitamin B2 grouped according to CRP concentrations ≤10, 11–80 and >80 mg/L were 2.2, 2.3 and 2.4 nmol/g Hb respectively (p < 0.001, 9% higher). The median red cell concentrations of vitamin B2 grouped according to albumin concentrations ≥35, 25–34 and <25 g/l were 2.1, 2.4 and 2.3 nmol/g Hb respectively (p < 0.001, 14% higher). The median concentrations of red cell vitamin B6 grouped according to CRP concentrations ≤10, 11–80 and >80 mg/L were 534, 548 and 767 pmol/g Hb respectively (p < 0.001, 44% higher). The median red cell concentrations of vitamin B6 grouped according to albumin concentrations ≥35, 25–34 and <25 g/l were 462, 644 and 840 pmol/g Hb respectively (p < 0.001, 82% higher). In contrast, the median plasma concentrations of ascorbic acid grouped according to CRP concentrations ≤10, 11–80 and >80 mg/L were 25.0, 15.0 and 6.0 μmol/l respectively (78% lower, p < 0.001). The median plasma concentrations of ascorbic acid grouped according to albumin concentrations ≥35, 25–34 and <25 g/l were 32.0, 13.0 and 5.0 μmol/l respectively (84% lower, p < 0.001). The median α-tocopherol/cholesterol grouped according to CRP concentrations ≤10, 11–80 and >80 mg/L were 5.9, 4.6 and 2.1 μmol/l respectively (64% lower, p < 0.001). The median α-tocopherol/cholesterol grouped according to albumin concentrations ≥35, 25–34 and <25 g/l were 6.0, 5.5 and 2.1 μmol/l respectively (65% lower, p < 0.001). Conclusion: Red cell concentrations of vitamins B1, B2 and B6 were not lower with an increasing systemic inflammatory response. In contrast, plasma concentrations of vitamin C and E were lower. Therefore, compared with plasma concentration, red cell concentrations of B1, B2 and B6 are likely to be more reliable measures of status in the presence of a systemic inflammatory response

Telomere homeostasis: interplay with magnesium

Telomere biology, a key component of the hallmarks of ageing, offers insight into dysregulation of normative ageing processes that accompany age-related diseases such as cancer. Telomere homeostasis is tightly linked to cellular metabolism, and in particular with mitochondrial physiology, which is also diminished during cellular senescence and normative physiological ageing. Inherent in the biochemistry of these processes is the role of magnesium, one of the main cellular ions and an essential cofactor in all reactions that use ATP. Magnesium plays an important role in many of the processes involved in regulating telomere structure, integrity and function. This review explores the mechanisms that maintain telomere structure and function, their influence on circadian rhythms and their impact on health and age-related disease. The pervasive role of magnesium in telomere homeostasis is also highlighted

Which circulating antioxidant vitamins are confounded by socioeconomic deprivation? The MIDSPAN family study

<p><b>Background:</b> Antioxidant vitamins are often described as having “independent” associations with risk of cancer, cardiovascular disease (CVD) and mortality. We aimed to compare to what extent a range of antioxidant vitamins and carotenoids are associated with adulthood and childhood markers of socioeconomic deprivation and to adverse lifestyle factors.</p> <p><b>Methods and Findings:</b> Socioeconomic and lifestyle measures were available in 1040 men and 1298 women from the MIDSPAN Family Study (30–59 years at baseline) together with circulating levels of vitamins A, C, E, and carotenoids (α-carotene, β-carotene, lutein and lycopene). Markers of socioeconomic deprivation in adulthood were consistently as strongly associated with lower vitamin C and carotenoid levels as markers of adverse lifestyle; the inverse association with overcrowding was particularly consistent (vitamin C and carotenoids range from 19.1% [95% CI 30.3–6.0] to 38.8% [49.9–25.3] lower among those in overcrowded residencies). These associations were consistent after adjusting for month, classical CVD risk factors, body mass index, physical activity, vitamin supplements, dietary fat and fibre intake. Similar, but weaker, associations were seen for childhood markers of deprivation. The association of vitamin A or E were strikingly different; several adult adverse lifestyle factors associated with higher levels of vitamin A and E, including high alcohol intake for vitamin A (9.5% [5.7–13.5]) and waist hip ratio for vitamin E (9.5% [4.8–14.4]), with the latter associations partially explained by classical risk factors, particularly cholesterol levels.</p> <p><b>Conclusions:</b> Plasma vitamin C and carotenoids have strong inverse associations with adulthood markers of social deprivation, whereas vitamin A and E appear positively related to specific adverse lifestyle factors. These findings should help researchers better contextualize blood antioxidant vitamin levels by illustrating the potential limitations associated with making causal inferences without consideration of social deprivation.</p&gt

Regression correction equation to adjust serum iron and ferritin concentrations based on C-reactive protein and albumin in patients receiving primary and secondary care

Background: Systemic inflammation, even at low levels, can greatly interfere with measures of iron status, making diagnosis of iron deficiency difficult. The objective of the present study was to create linear regression correction equations to adjust serum ferritin and iron concentrations based on measurements of the acute-phase proteins C-reactive protein (CRP) and albumin. Methods: Data from a cohort (1) of patients (n = 7226) in primary and secondary care who had serum ferritin, iron, CRP, and albumin measured at the same time point were examined. Linear regression coefficients were calculated for CRP and albumin with serum iron and ferritin as the outcome variables. Patients with ferritin <15 µg/L or serum iron <10 µmol/L were categorized as iron deficient. The equation was then applied to a cohort (2) of patients with colorectal cancer who had ferritin and iron measured preoperatively ( n = 356). Results: In cohort 1 there was a significant difference in the proportions of patients with serum ferritin <15 µg/L and serum iron <10 µmol/L, respectively, when the unadjusted (7% and 55%), adjusted based on CRP alone (13% and 26%), adjusted based on albumin alone (11% and 37%), and adjusted based on both CRP and albumin (24% and 15%) values were compared (both P < 0.001). In cohort 2 there was a significant difference in the proportions of patients with serum ferritin <15 µg/L and serum iron <10 µmol/L, respectively, when the unadjusted (28% and 66%), adjusted based on CRP alone (39% and 57%), adjusted based on albumin alone (39% and 59%), and adjusted based on both CRP and albumin (46% and 44%) values were compared (P < 0.001 and P < 0.004). Conclusions: In both cohorts the greatest increase in the proportion of patients meeting definitions of iron deficiency was found when adjustment was made for both CRP and albumin together. Even low levels of inflammation had a significant effect on serum iron and ferritin values