The genetic and epigenetic profile of serum S100ß in the Lothian Birth Cohort 1936 and its relationship to Alzheimer's disease.

Background: Circulating S100 calcium-binding protein (S100ß) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100ß and its potential causal associations with Alzheimer's disease, we carried out genome- and epigenome-wide association studies (GWAS/EWAS) of serum S100ß levels in older adults and performed Mendelian randomisation with Alzheimer's disease. Methods: GWAS (N=769, mean age 72.5 years, sd = 0.7) and EWAS (N=722, mean age 72.5 years, sd = 0.7) of S100ß levels were performed in participants from the Lothian Birth Cohort 1936. Conditional and joint analysis (COJO) was used to identify independent loci. Expression quantitative trait locus (eQTL) analyses were performed for lead loci that had genome-wide significant associations with S100ß. Bidirectional, two-sample Mendelian randomisation was used to test for causal associations between S100ß and Alzheimer's disease. Colocalisation between S100ß and Alzheimer's disease GWAS loci was also examined. Results: We identified 154 SNPs from chromosome 21 that associated (P<5x10 -8) with S100ß protein levels. The lead variant was located in the S100ß gene (rs8128872, P=5.0x10 -17). We found evidence that two independent causal variants existed for both transcription of S100ß and S100ß protein levels in our eQTL analyses . No CpG sites were associated with S100ß levels at the epigenome-wide significant level (P<3.6x10 -8); the lead probe was cg06833709 (P=5.8x10 -6), which mapped to the LGI1 gene. There was no evidence of a causal association between S100ß levels and Alzheimer's disease or vice versa and no evidence for colocalisation between S100ß and Alzheimer's disease loci. Conclusions: These data provide insight into the molecular regulators of S100ß levels. This context may aid in understanding the role of S100ß in brain inflammation and neurological disease.

Micronutrients in critically ill patients with severe acute kidney injury - a prospective study.

Malnutrition is common in patients with acute kidney injury (AKI) and the risk of mortality is high, especially if renal replacement therapy is needed. Between April 2013 through April 2014, we recruited critically ill adult patients (≥18 years) with severe AKI in two University hospitals in London, UK, and measured serial plasma concentrations of vitamin B1, B6, B12, C and D, folate, selenium, zinc, copper, iron, carnitine and 22 amino acids for six consecutive days. In patients receiving continuous renal replacement therapy (CRRT), the concentrations of the same nutrients in the effluent were also determined. CRRT patients (n = 31) had lower plasma concentrations of citrulline, glutamic acid and carnitine at 24 hrs after enrolment and significantly lower plasma glutamic acid concentrations (74.4 versus 98.2 µmol/L) at day 6 compared to non-CRRT patients (n = 24). All amino acids, trace elements, vitamin C and folate were detectable in effluent fluid. In >30% of CRRT and non-CRRT patients, the plasma nutrient concentrations of zinc, iron, selenium, vitamin D3, vitamin C, trytophan, taurine, histidine and hydroxyproline were below the reference range throughout the 6-day period. In conclusion, altered micronutrient status is common in patients with severe AKI regardless of treatment with CRRT.

Longitudinal serum S100ß and brain aging in the Lothian Birth Cohort 1936.

Elevated serum and cerebrospinal fluid concentrations of S100ß, a protein predominantly found in glia, are associated with intracranial injury and neurodegeneration, although concentrations are also influenced by several other factors. The longitudinal association between serum S100ß concentrations and brain health in nonpathological aging is unknown. In a large group (baseline N = 593; longitudinal N = 414) of community-dwelling older adults at ages 73 and 76 years, we examined cross-sectional and parallel longitudinal changes between serum S100ß and brain MRI parameters: white matter hyperintensities, perivascular space visibility, white matter fractional anisotropy and mean diffusivity (MD), global atrophy, and gray matter volume. Using bivariate change score structural equation models, correcting for age, sex, diabetes, and hypertension, higher S100ß was cross-sectionally associated with poorer general fractional anisotropy (r = -0.150, p = 0.001), which was strongest in the anterior thalamic (r = -0.155, p < 0.001) and cingulum bundles (r = -0.111, p = 0.005), and survived false discovery rate correction. Longitudinally, there were no significant associations between changes in brain imaging parameters and S100ß after false discovery rate correction. These data provide some weak evidence that S100ß may be an informative biomarker of brain white matter aging.

Short-term abstinence from alcohol and changes in cardiovascular risk factors, liver function tests and cancer-related growth factors: a prospective observational study.

OBJECTIVE: To assess changes in metabolic risk factors and cancer-related growth factors associated with short-term abstinence from alcohol. DESIGN: Prospective, observational study. SETTING: Single tertiary centre. PARTICIPANTS: Healthy subjects were recruited based on intention to: (1) abstain from alcohol for 1 month (abstinence group), or (2) continue to drink alcohol (control group). Inclusion criteria were baseline alcohol consumption >64 g/week (men) or >48 g/week (women). Exclusion criteria were known liver disease or alcohol dependence. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was change in insulin resistance (homeostatic model assessment (HOMA) score). Secondary outcomes were changes in weight, blood pressure (BP), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and liver function tests. Primary and secondary outcomes were adjusted for changes in diet, exercise and cigarette smoking. RESULTS: The abstinence group comprised 94 participants (mean age 45.5 years, SD ±1.2) and the control group 47 participants (mean age 48.7 years, SD ±1.8). Baseline alcohol consumption in the abstinence group was 258.2 g/week, SD ±9.4, and in the control group 233.8 g, SD ±19.0. Significant reductions from baseline in the abstinence group (all p<0.001) were found in: HOMA score (-25.9%, IQR -48.6% to +0.3%), systolic BP (-6.6%, IQR -11.8% to 0.0%), diastolic BP (-6.3%, IQR -14.1% to +1.3%), weight (-1.5%, IQR -2.9% to -0.4%), VEGF (-41.8%, IQR -64.9% to -17.9%) and EGF (-73.9%, IQR -86.1% to -36.4%). None of these changes were associated with changes in diet, exercise or cigarette smoking. No significant changes from baseline in primary or secondary outcomes were noted in the control group. CONCLUSION: These findings demonstrate that abstinence from alcohol in moderate-heavy drinkers improves insulin resistance, weight, BP and cancer-related growth factors. These data support an independent association of alcohol consumption with cancer risk, and suggest an increased risk of metabolic diseases such as type 2 diabetes and fatty liver disease.

The effect of ethnicity on the performance of protein-creatinine ratio in the prediction of significant proteinuria in pregnancies at risk of or with established hypertension: an implementation audit and cost implications.

INTRODUCTION: The replacement of 24-h urine collection by protein-creatinine ratio (PCR) for the diagnosis of preeclampsia has been recently recommended. However, the literature is conflicting and there are concerns about the impact of demographic characteristics on the performance of PCR. MATERIAL AND METHODS: This was an implementation audit of the introduction of PCR in a London Tertiary obstetric unit. The performance of PCR in the prediction of proteinuria ≥300 mg/day was assessed in 476 women with suspected preeclampsia who completed a 24-h urine collection and an untimed urine sample for PCR calculation. Multivariate logistic regression was used to assess the independent predictors of significant proteinuria. RESULTS: In a pregnant population, ethnicity and PCR are the main predictors of ≥300 mg proteinuria in a 24-h urine collection. A PCR cut-off of 30 mg/mmol would have incorrectly classified as non-proteinuric, 41.4% and 22.9% of black and non-black women, respectively. Sensitivity of 100% is achieved at cut-offs of 8.67 and 20.56 mg/mmol for black and non-black women, respectively. Applying these levels as a screening tool to inform the need to perform a 24-h urine collection in 1000 women, would lead to a financial saving of €2911 in non-black women and to an additional cost of €3269 in black women. CONCLUSIONS: Our data suggest that a move from screening for proteinuria with a 24-h urine collection to screening with urine PCR is not appropriate for black populations. However, the move may lead to cost-saving if used in the white population with a PCR cut-off of 20.5.

The association of depressive symptoms and diabetes distress with glycaemic control and diabetes complications over 2 years in newly diagnosed type 2 diabetes: a prospective cohort study.

AIMS/HYPOTHESIS: We examined the associations between depressive symptoms and diabetes distress with glycaemic control and diabetes complications over 2 years, after diagnosis of type 2 diabetes. METHODS: In a multi-ethnic, primary care cohort (n = 1735) of adults, all with recent (<6 months) diagnosis of type 2 diabetes, we measured the associations between depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score ≥10) and diabetes distress (Problem Areas in Diabetes [PAID] score ≥40), with change in 2 year HbA1c as the primary outcome and with incident rates of diabetes complications as secondary outcomes. Multivariate models were used to account for potential confounders. RESULTS: Of the 1651 participants (95.2%) of the total primary care cohort with available baseline PHQ-9 and PAID scores, mean ± SD age was 56.2 ± 11.1 years, 55.1% were men and 49.1% were of non-white ethnicity; 232 (14.1%) and 111 (6.7%) had depressive symptoms and diabetes distress, respectively. After adjustment for confounders, depressive symptoms were not associated with worsening HbA1c. After adjustment for age, sex, ethnicity, vascular risk factors and diabetes treatments, depressive symptoms were associated with increased risk of incident macrovascular complications (OR 2.78 [95% CI 1.19, 6.49], p = 0.018) but not microvascular complications. This was attenuated (p = 0.09) after adjustment for IL-1 receptor antagonist concentration. Diabetes distress was not associated with worsening HbA1c or incident complications. CONCLUSIONS/INTERPRETATION: In the first 2 years of type 2 diabetes, the effect of depressive symptoms and diabetes distress on glycaemic control is minimal. There was, however, an association between depressive symptoms and incidence of macrovascular complications. Elevated innate inflammation may be common to both depression and macrovascular diabetes complications, but these findings require replication.

A randomized double-blind placebo-controlled trial of a multi-strain probiotic in treatment of symptomatic uncomplicated diverticular disease.

BACKGROUND: Diverticular disease is a significant burden on healthcare systems that is managed, surgically or medically, mainly as an emergency or acute condition. There are no standardized treatment recommendations for symptomatic uncomplicated disease. We hypothesized that a probiotic would reduce abdominal pain in such patients. METHODS: We conducted a single-center, double-blind, placebo-controlled trial of probiotic treatment (Symprove) in adult patients with moderate-to-severe chronic, non-acute symptomatic diverticular disease. 143 patients were randomized to receive 1 mL/kg/day of probiotic liquid (N = 72) or placebo (N = 71) daily for 3 months. The primary endpoint was abdominal pain severity. Secondary endpoints consisted of the change in the frequency of eight abdominal symptoms and the level of intestinal inflammation (fecal calprotectin). RESULTS: 120 patients completed the trial. Abdominal pain score, the primary end point, decreased in both groups, but no significant difference between the groups was found (P = 0.11). In relation to placebo, the probiotic significantly decreased the frequency of four of the eight secondary endpoints: constipation, diarrhea, mucorrhea, and back pain (P < 0.04). No significant differences were found in frequency of abdominal pain, PR bleeding, dysuria, and bloating. CONCLUSIONS: Multi-strain liquid probiotic did not improve abdominal pain scores significantly, but significantly improved the frequency of four other symptoms associated with chronic, non-acute symptomatic diverticular disease.

Composite biomarker panel for prediction of severity and diagnosis of acute GVHD with T-cell-depleted allogeneic stem cell transplants-single centre pilot study.

AIMS: Acute graft-versus-host disease (aGVHD) is a leading cause of morbidity and mortality following allogeneic haematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the clinical utility of a composite biomarker panel to help identify individuals at risk of developing aGVHD, and to help predict and differentiate between severity of aGVHD following T-cell-depleted allogeneic HSCT. METHODS: We retrospectively analysed our cohort of biopsy confirmed patients with aGVHD, who underwent T-cell-depleted HSCT and matched them with negative controls without any evidence of aGVHD. Post-transplant serum samples on days 0 and 7 and at onset of aGVHD were analysed for elafin, regenerating islet-derived 3-α, soluble tumour necrosis factor receptor-1, soluble interleukin-2 receptor-α and hepatocyte growth factor. Biomarker data were combined as composite panels A-F (table 2) using logistic regression analysis. Receiver operating characteristic analysis was performed to study sensitivity and specificity of the composite panels. RESULTS: Our composite biomarker panels significantly differentiated between aGVHD and no GVHD patients at time of onset (panel E) and reliably predicted severity of GVHD grades at days 0 and 7 post-transplant (panels B and D). The area under the curve for the composite panel at time of onset was 0.65 with specificity, sensitivity, positive and negative predictive values of 100%, 55.6%, 100% and 78.9%, respectively (p=0.03). CONCLUSIONS: This pilot data support the usefulness of these composite biomarker panels in the prediction of severity and diagnosis of aGVHD in patients undergoing T-cell-depleted reduced intensity allogeneic HSCT.

Elevated fasting and postprandial C-terminal telopeptide after Roux-en-Y gastric bypass.

Background Roux-en-Y gastric bypass increases circulating bile acid concentrations, known mediators of postprandial suppression of markers of bone resorption. Long-term data, however, indicate that Roux-en-Y gastric bypass confers an increased risk of bone loss on recipients. Methods Thirty-six obese individuals, median age 44 (26-64) with median body mass index at baseline of 42.5 (40.4-46) were studied before and 15 months after Roux-en-Y gastric bypass. After an overnight fast, patients received a 400 kcal mixed meal. Blood samples were collected premeal then at 30-min periods for 120 min. Pre and postmeal samples were analysed for total bile acids, parathyroid hormone and C-terminal telopeptide. Results Body weight loss post Roux-en-Y gastric bypass was associated with a median 4.9-fold increase in peak postprandial total bile acid concentration, and a median 2.4-fold increase in cumulative food evoked bile acid response. Median fasting parathyroid hormone, postprandial reduction in parathyroid hormone and total parathyroid hormone release over 120 min remained unchanged after surgery. After surgery, median fasting C-terminal telopeptide increased 2.3-fold, peak postprandial concentrations increased 3.8-fold and total release was increased 1.9-fold. Conclusions Fasting and postprandial total bile acids and C-terminal telopeptide are increased above reference range after Roux-en-Y gastric bypass. These changes occur in spite of improved vitamin D status with supplementation. These results suggest that post-Roux-en-Y gastric bypass increases in total bile acids do not effectively oppose an ongoing resorptive signal operative along the gut-bone axis. Serial measurement of C-terminal telopeptide may be of value as a risk marker for long-term skeletal pathology in patients post Roux-en-Y gastric bypass.

Early change in faecal calprotectin predicts primary non-response to anti-TNFα therapy in Crohn's disease.

OBJECTIVE: The early identification of primary non-response to anti-TNFα therapy facilitates the timely management of patients with Crohn's disease (CD). A recent, pilot study to detect prognostic markers of early response to anti-TNFα therapy identified the two genes coding for the calprotectin subunits (S100A8, S100A9) to be among the most highly expressed gene transcripts in non-responders. This study tests the hypothesis that measurements of faecal calprotectin (FCAL) pre- and post-anti-TNFα induction can predict primary non-response. METHODS: Retrospective study of 32 CD patients treated over a two-year period. Outcomes were assessed at 6 months based on clinical activity scores and the use of corticosteroids: (a) remission: Harvey-Bradshaw index (HBI) < 5, off corticosteroids >2 months; (b) response: drop in HBI >3, off corticosteroids; (c) non-response: ΔFCAL (and ΔCRP, respectively) was calculated as (FCAL post-induction - FCAL pre-induction) × 100/FCAL pre induction. RESULTS: At 6 months, 23 (72%) patients had responded (median (interquartile range) HBI: 4 (3-5), FCAL: 55 (27-146)), 17 (73%) of whom were in remission [HBI: 3 (2.5-4) and FCAL: 42 (16-115)]. There was a significant difference in the ΔFCAL from baseline to post-induction in the three groups (p < 0.0001). Comparing non-responders to combined response and remission groups, the AUC of ΔFCAL to predict outcome at 6 months was 0.97. Using ROC analysis, a Δ70% returned a sensitivity and specificity of 99% and 96%, respectively (likelihood ratio, LR= 23). ΔCRP did not predict 6 months outcomes. CONCLUSIONS: A drop in FCAL <70% after induction predicts primary non-response to anti-TNFα in CD.

Biologic Variability of Soluble ST2 in Patients With Stable Chronic Heart Failure and Implications for Monitoring.

Soluble ST2 (sST2) is a novel biomarker implicated in myocardial remodeling and fibrosis. Recent studies in normal subjects have suggested that the biologic variability (BV) of sST2 is significantly lower than that of the B-type natriuretic peptides and N-terminal pro B-type natriuretic peptide (NTproBNP). It may, consequently, be a better biomarker for monitoring patients with chronic heart failure (CHF). To date, no published studies have examined the BV of sST2 in a heart failure population. Blood samples from 50 outpatients with pharmacologically optimized stable CHF and persistent left ventricular dysfunction (ejection fraction <40%) were collected at baseline, 1 hour, 1 month, 3 months, and 6 months. Using log-transformed data, mean intra-individual coefficients of variation (CVI) and subsequent reference change values were calculated for both NTproBNP and sST2. Results demonstrate significantly lower CVI and reference change values for sST2 compared with NTproBNP at 1 month (12.02 [36%] vs 36.75 [103%]), p <0.001, 3 months (12.23 [36%] vs 40.98 [114%]), p <0.001, and 6 months (16.41 [47%] vs 46.02 [128%]), p <0.001. In conclusion, the BV of sST2 is significantly lower than that of NTproBNP in patients with CHF. These results support previous indications that sST2 may be a better biomarker for monitoring such patients.

Clinical relevance of trace element measurement in patients on initiation of parenteral nutrition.

Background and Aims Serum zinc, copper and selenium are measured in patients prior to commencing on parenteral nutrition; however, their interpretation can be difficult due to acute phase reactions. We assessed (i) the relationship of raised C-reactive protein with trace elements and albumin (ii) benefits of measuring trace elements when C-reactive protein is raised in patients requiring short-term parenteral nutrition. Methods Samples were collected for zinc, copper, selenium and albumin at baseline and then every two weeks and correlated with C-reactive protein results in patients on parenteral nutrition. Results were categorized into four groups based on the C-reactive protein concentrations: (i) <20 mg/L, (ii) 20-39 mg/L, (iii) 40-79 mg/L and (iv) ≥80 mg/L. Results In 166 patients, zinc, selenium and albumin correlated (Spearman's) negatively with C-reactive protein; r = -0.26, P < 0.001 (95% CI -0.40 to -0.11), r = -0.44, P < 0.001 (-0.56 to -0.29) and r = -0.22 P = 0.005 (-0.36 to -0.07), respectively. Copper did not correlate with C-reactive protein (r = 0.09, P = 0.25 [-0.07 to 0.25]). Comparison of trace elements between the four groups showed no difference in zinc and copper (both P > 0.05), whereas selenium and albumin were lower in the group with C-reactive protein > 40 mg/L ( P < 0.05). Conclusion In patients on short-term parenteral nutrition, measurement of C-reactive protein is essential when interpreting zinc and selenium but not copper results. Routine measurement of trace elements prior to commencing parenteral nutrition has to be considered on an individual basis in patients with inflammation.

Fecal calprotectin in inflammatory bowel disease.

Inflammatory bowel disease (IBD) and irritable bowel syndrome share many symptoms. While irritable bowel syndrome is a functional bowel disorder for which no specific treatment is available, the range of effective therapies for IBD is evolving rapidly. Accurate diagnosis of IBD is therefore essential. Clinical assessment, together with various imaging modalities and endoscopy, has been the mainstay of diagnosis for many years. Fecal biomarkers of gastrointestinal inflammation have appeared in the past decade, of which calprotectin, a neutrophil cytosolic protein, has been studied the most. Crohn's disease and ulcerative colitis are chronic remitting and relapsing diseases, and objective assessment of disease activity and response to treatment are important. This review focuses on the use of fecal calprotectin measurements in the diagnosis and monitoring of patients with IBD.

A Multicenter Prospective Study to Investigate the Diagnostic Accuracy of the SeHCAT Test in Measuring Bile Acid Malabsorption: Research Protocol.

BACKGROUND: Bile acid malabsorption (BAM) is one possible explanation for chronic diarrhea. BAM may be idiopathic, or result from ileal resection or inflammation including Crohn's disease, or may be secondary to other conditions, including cholecystectomy, peptic ulcer surgery, and chronic pancreatitis. No "gold standard" exists for clinical diagnosis of BAM, but response to treatment with a bile acid sequestrant (BAS) is often accepted as confirmation. The SeHCAT (tauroselcholic [selenium-75] acid) test uses a radiolabeled synthetic bile acid and provides a diagnostic test for BAM, but its performance against "trial of treatment" is unknown. Fibroblast growth factor 19 (FGF-19) and 7-alpha-hydroxy-4-cholesten-3-one (C4) also offer potential new biomarkers of BAM. OBJECTIVE: This protocol describes a multicenter prospective study to evaluate the diagnostic accuracy of SeHCAT and 2 biomarkers in predicting BAM as assessed by trial of treatment. METHODS: Participating gastroenterology centers should have a minimum workload of 30 SeHCAT patients per annum. Patients should not be pregnant, on medication that could confound follow-up, or have any severe comorbidity. All eligible patients attending a gastrointestinal appointment will be invited to participate. On attending the SeHCAT test, blood and fecal samples will be collected for analysis of FGF-19 by enzyme-linked immunosorbent assay and for C4 and fractionated bile acids by liquid chromatography-mass spectrometry. A capsule containing radiolabeled SeHCAT will be administered orally and a scan performed to measure SeHCAT activity. Patients will return on day 7 to undergo a second scan to measure percentage SeHCAT retention. The test result will be concealed from clinicians and patients. BAS will be dispensed to all patients, with a follow-up gastroenterologist appointment at 2 weeks for clinical assessment of treatment response and adherence. Patients responding positively will continue treatment for a further 2 weeks and all patients will have a final follow-up at 8 weeks. The diagnostic accuracy of the SeHCAT test and biomarkers will be analyzed at different thresholds using sensitivity, specificity, positive and negative predictive value, likelihood ratios, and area under the curve in a sample of 600 patients. Multivariable logistic regression models will be used to assess the association between presence of BAM and continuous SeHCAT retention levels after adjustment for confounders. RESULTS: Funding is being sought to conduct this research. CONCLUSIONS: The SeHCAT test for diagnosis of BAM has been in common use in the United Kingdom for more than 30 years and an evidence-based assessment of its accuracy is overdue. The proposed study has some challenges. Some forms of BAS treatment are unpleasant due to the texture and taste of the resin powder, which may negatively affect recruitment and treatment adherence. Trial of treatment is not as "golden" a standard as would be ideal, and itself warrants further study.

Changes in biomarkers of bone turnover in an aripiprazole add-on or switching study.

BACKGROUND: The association between mental illness and osteoporosis and fractures is particularly pronounced in psychotic disorders. Antipsychotic use has previously been described to affect bone density. METHOD: A 52-week follow-up of patients switched to aripiprazole or with aripiprazole added on, conducting a specific analysis of markers of bone turnover: urinary NTX (a biomarker of bone resorption) and serum BSAP (a biomarker of bone formation). Baseline and serial measurements of bone markers NTX, BSAP and of hormones prolactin, oestrogen and testosterone were done at weeks 0 and 1, 2, 6, 12, 26 and 52, respectively. RESULTS: NTX concentration reduced over time but this did not reach significance in the whole group (log-NTX: ß=-0.0012, p=0.142). For BSAP the addition of or replacement with aripiprazole produced a significant reduction (log-BSAP: ß=-0.00039, p=0.002). Analysis with prolactin similarly showed a significant reduction (log-prolactin: ß=-0.0024, p<0.001); other hormones did not change significantly. Sensitivity analysis to compare the switchers to aripiprazole versus the "add-on" showed that the former group had a significant reduction in NTX. CONCLUSIONS: We found that switching to aripiprazole was associated with changes in molecular biomarkers of bone resorption, indicating a more favourable profile for bone health.

NADPH oxidase 4 regulates homocysteine metabolism and protects against acetaminophen-induced liver damage in mice.

Glutathione is the major intracellular redox buffer in the liver and is critical for hepatic detoxification of xenobiotics and other environmental toxins. Hepatic glutathione is also a major systemic store for other organs and thus impacts on pathologies such as Alzheimer's disease, Sickle Cell Anaemia and chronic diseases associated with aging. Glutathione levels are determined in part by the availability of cysteine, generated from homocysteine through the transsulfuration pathway. The partitioning of homocysteine between remethylation and transsulfuration pathways is known to be subject to redox-dependent regulation, but the underlying mechanisms are not known. An association between plasma Hcy and a single nucleotide polymorphism within the NADPH oxidase 4 locus led us to investigate the involvement of this reactive oxygen species- generating enzyme in homocysteine metabolism. Here we demonstrate that NADPH oxidase 4 ablation in mice results in increased flux of homocysteine through the betaine-dependent remethylation pathway to methionine, catalysed by betaine-homocysteine-methyltransferase within the liver. As a consequence NADPH oxidase 4-null mice display significantly lowered plasma homocysteine and the flux of homocysteine through the transsulfuration pathway is reduced, resulting in lower hepatic cysteine and glutathione levels. Mice deficient in NADPH oxidase 4 had markedly increased susceptibility to acetaminophen-induced hepatic injury which could be corrected by administration of N-acetyl cysteine. We thus conclude that under physiological conditions, NADPH oxidase 4-derived reactive oxygen species is a regulator of the partitioning of the metabolic flux of homocysteine, which impacts upon hepatic cysteine and glutathione levels and thereby upon defence against environmental toxins.

Predicting refeeding hypophosphataemia: insulin growth factor 1 (IGF-1) as a diagnostic biochemical marker for clinical practice.

BACKGROUND: Refeeding syndrome (RS) is a potentially fatal condition that can occur following the re-introduction of nutrition after a period of starvation. Hypophosphataemia following the reintroduction of nutrition is often the only reliable biochemical marker of RS. Refeeding index (RI) generated from baseline insulin-like growth factor-1 (IGF-1) and leptin has been proposed as a useful biochemical marker for the identification of patients at risk of developing refeeding hypophosphataemia (RH). METHODS: A prospective study included 52 patients referred for parenteral nutrition (PN). The sensitivity and specificity of IGF-1 measured using a sensitive assay was compared to the RI in predicting the development of RH (a ≥ 30% drop in PO4 during the first 36-h of PN administration). Leptin and IGF-1 were analysed on baseline samples using a quantitative enzyme-linked immunoassay. Daily blood samples were collected from all patients for routine biochemistry for the full duration of PN administration. RESULTS: High sensitivity IGF-1 measurement alone was comparable with the RI, using receiver-operating characteristic (ROC) curve analysis, with areas under the curve being 0.79 and 0.80, respectively, and superior to leptin alone (0.72) for predicting ≥ 30% drop in PO4. The cut-off value for IGF-1 that gave best sensitivity (91% [95% CI 75-98%]) and specificity (65% [95% CI 41-85%]) was 63.7 µg/L, with a likelihood ratio of 2.59. CONCLUSION: Baseline IGF-1 is an objective, sensitive and specific biochemical marker in identifying patients who are at high risk of developing RH prior to PN administration and therefore may have a role in clinical practice.

Serial soluble ST2 for the monitoring of pharmacologically optimised chronic stable heart failure.

BACKGROUND: Soluble ST2 (sST2) is an emerging biomarker of cardiac remodelling and fibrosis. Studies indicate that it is predictive of mortality in acutely decompensated heart failure. The role of sST2 in chronic heart failure (CHF) is less well defined. No studies have examined serial measurements in optimised patients as a potential monitoring tool. This study aimed to prospectively determine the prognostic utility of serial sST2 in patients with pharmacologically optimised stable CHF. METHODS: 41 patients with pharmacologically optimised CHF and left ventricular ejection fraction ≤40% were recruited. Clinical review and blood sampling took place at baseline, and one, three and six months. N-terminal pro-brain natriuretic peptide (NTproBNP), sST2 and renal profile were measured on all samples. 12 lead electrocardiogram (ECG) was performed at baseline. Decompensation was defined as a composite endpoint of cardiovascular admission or worsening renal function (≥25% increase in serum creatinine from baseline). RESULTS: Receiver operator curve analysis of percentage change in sST2 from baseline to six months was strongly reflective of decompensation with area under the curve (AUC) of 0.778. This was significantly better than NTproBNP (AUC 0.425; p=0.013). Correlation of baseline concentrations to surface ECG showed that both sST2 and NTproBNP were positively correlated with duration of the QRS wave, with higher level of significance demonstrated by sST2 (0.415 (p=0.007) and 0.362 (p=0.020) respectively). CONCLUSIONS: Percentage changes in sST2 are better able to predict cardiovascular admission or worsening renal function in patients with pharmacologically optimised CHF than NTproBNP. Compared with NTproBNP, sST2 appears to be a promising candidate for monitoring these patients.

The association between depressive symptoms and systemic inflammation in people with type 2 diabetes: findings from the South London Diabetes Study.

OBJECTIVE: The prevalence of depression and depressive symptoms is increased twofold in people with type 2 diabetes compared with the general population and is associated with worse biomedical outcomes and increased mortality. Type 2 diabetes, cardiovascular disease, and depression in nondiabetes subjects are independently associated with raised concentrations of circulating inflammatory markers, but it is not known if a similar association is observed in type 2 diabetes. We tested the hypothesis that higher depressive symptom scores in newly diagnosed type 2 diabetes patients were associated with higher concentrations of inflammatory markers. RESEARCH DESIGN AND METHODS: Depressive symptoms in adults with newly diagnosed type 2 diabetes recruited from primary care were assessed using the Patient Health Questionnaire-9. Twelve markers of inflammation (C-reactive protein [hs-CRP], interleukin-4 [IL-4], IL-6, IL-10, vascular endothelial growth factor [VEGF], tumor necrosis factor-α [TNF-α], IL-1ß, IL-1 receptor antagonist [IL-1RA], monocyte chemotactic protein-1 [MCP-1], white blood cell count [WBC], adiponectin, and triglyceride [TG]) were measured. Covariates included sociodemographic factors, adiposity, macrovascular disease, HbA1c, and prescribed medication. The association between each inflammatory marker and depressive symptom score was estimated by multiple linear regression. RESULTS: The baseline cohort consisted of 1,790 participants. After adjusting for covariates, CRP (B = 0.13, P < 0.001), IL-1ß (B = 0.06, P = 0.047), IL-1RA (B = 0.13, P < 0.001), MCP-1 (B = 0.11, P = 0.001), WBC (B = 0.13, P < 0.001), and TG (B = 0.10, P < 0.001) were associated with depressive symptoms. CONCLUSIONS: Increased inflammation may be involved in the pathogenesis of depressive symptoms in type 2 diabetes and contribute to the increased risk of complications and mortality in this group.