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.

Total protein, albumin and low-molecular-weight protein excretion in HIV-positive patients.

BACKGROUND: Chronic kidney disease is common in HIV positive patients and renal tubular dysfunction has been reported in those receiving combination antiretroviral therapy (cART). Tenofovir (TFV) in particular has been linked to severe renal tubular disease as well as proximal tubular dysfunction. Markedly elevated urinary concentrations of retinal-binding protein (RBP) have been reported in patients with severe renal tubular disease, and low-molecular-weight proteins (LMWP) such as RBP may be useful in clinical practice to assess renal tubular function in patients receiving TFV. We analysed 3 LMWP as well as protein and albumin in the urine of a sample of HIV positive patients. METHODS: In a cross-sectional fashion, total protein, albumin, RBP, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) were quantified in random urine samples of 317 HIV positive outpatients and expressed as the ratio-to-creatinine (RBPCR, CCR and NGALCR). Exposure to cART was categorised as none, cART without TFV, and cART containing TFV and a non-nucleoside reverse-transcriptase-inhibitor (TFV/NNRTI) or TFV and a protease-inhibitor (TFV/PI). RESULTS: Proteinuria was present in 10.4 % and microalbuminuria in 16.7 % of patients. Albumin accounted for approximately 10 % of total urinary protein. RBPCR was within the reference range in 95 % of patients while NGALCR was elevated in 67 % of patients. No overall differences in urine protein, albumin, and LMWP levels were observed among patients stratified by cART exposure, although a greater proportion of patients exposed to TFV/PI had RBPCR >38.8 µg/mmol (343 µg/g) (p = 0.003). In multivariate analyses, black ethnicity (OR 0.43, 95 % CI 0.24, 0.77) and eGFR <75 mL/min/1.73 m2 (OR 3.54, 95 % CI 1.61, 7.80) were independently associated with upper quartile (UQ) RBPCR. RBPCR correlated well to CCR (r2 = 0.71), but not to NGALCR, PCR or ACR. CONCLUSIONS: In HIV positive patients, proteinuria was predominantly of tubular origin and microalbuminuria was common. RBPCR in patients without overt renal tubular disease was generally within the reference range, including those receiving TFV. RBP therefore appears a promising biomarker for monitoring renal tubular function in patients receiving TFV and for distinguishing patients with normal tubular function or mild tubular dysfunction from those with severe renal tubular disease or Fanconi syndrome.

Substance use by liver transplant candidates: an anonymous urinalysis study.

Toxicological urinalysis is a highly sensitive and specific test that detects recent substance use. It has been established for substance misuse treatment but has not been routinely used at liver transplantation (LT) centers. Patients with a history of substance misuse are required to be abstinent from alcohol and illicit drugs before they are listed for LT. In this cross-sectional study, we sought to determine the prevalence of recent substance use in LT candidates via toxicological urinalysis. One hundred nine adults who were admitted for an LT assessment provided data, and they were categorized by the etiology of their liver disease [alcohol-related liver disease (ALD), hepatitis C virus (HCV), or other liver diseases]. Urine was toxicologically screened for drugs and their metabolites as well as the urinary alcohol metabolites ethyl glucuronide and ethyl sulfate. The prevalence of alcohol metabolites in patients with ALD was 20%. Licit and illicit substances together provided a positive toxicological result in 30% of the patients. Positive results were more common among patients with HCV (40%) and ALD (38%) versus patients with other liver diseases (18%). During the clinical assessment, 4% of the patients with ALD or HCV self-reported current alcohol or illicit drug use. These results correspond to the findings of other studies and emphasize the uncertainty of self-reported substance use data for LT candidates.

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.

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.

Divergent effects of angiotensin-converting enzyme inhibition on blood pressure and endothelial function in obese humans.

Endothelial dysfunction is a pivotal early event in the development of atherosclerosis and a characteristic feature of obesity. This study was designed to investigate the effect of angiotensin-converting enzyme (ACE) inhibition on endothelial function in people who were obese but otherwise healthy. We performed a double-blind, randomised, placebo-controlled study examining the effect of the ACE inhibitor perindopril (4 mg per day) on flow-mediated vasodilatation (FMD) of the brachial artery, arterial blood pressure, glucose homeostasis and inflammatory cytokines. Eighteen obese subjects (all body mass index > 30 kg/m2) were randomised to receive perindopril or placebo for four weeks. Perindopril led to a fall in systolic blood pressure from 131 (standard error of mean [SEM] 3) to 117(5) mmHg and diastolic blood pressure from 74(4) mmHg to 68(4) mmHg, both p<0.001. Despite this fall in blood pressure, ACE inhibition had no effect on FMD, 8.2 (1.2)% versus 8.3 (1.5)%, p=0.9. ACE inhibition had no effect on insulin, lipids or circulating cytokines. In healthy obese humans, despite a significant reduction in blood pressure, ACE inhibition had no effect on FMD.

Effects of folic acid supplementation on psychomotor performance and hemorheology in healthy elderly subjects.

Cognitive impairment is associated with increased blood concentrations of homocysteine and high blood viscosity. Previous studies have shown that vitamin B supplementation reduces homocysteine and enhances cognitive function in patients with mild dementia and low serum folic acid. However, whether folic acid enhances cognitive function in elderly subjects without dementia and normal serum folic acid is unknown. Twenty-four healthy elderly subjects (age 73.0+/-5.6 years, mean+/-S.D.) with normal serum folic acid (6.3+/-2.4 microg/l) and Mini Mental State Examination (MMSE) >27/30 were randomized to 4-week treatment with folic acid 5mg/day or placebo in a randomized, placebo-controlled, parallel-group study. Continuous Attention Test (CAT), Four-Choice Reaction Time (FCRT), Digit-Symbol Substitution (DSS), Scanning Memory Sets (SMS), and blood viscosity for different shear rates were measured before and after treatment. Folic acid supplementation induced a significant increase in serum folic acid levels (+13.8 versus +1.6 microg/l, p<0.001) and fall in homocysteine levels (-1.91 versus -0.41 micromol/l, p=0.05) compared to placebo. However, there was no significant change in CAT, FCRT, DSS, SMS, and blood viscosity between the two groups. Short-term folic acid supplementation does not enhance psychomotor performance or reduce blood viscosity in healthy elderly subjects with normal serum folic acid levels and preserved cognitive function.

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.

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.

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.

Endothelial function and weight loss in obese humans.

BACKGROUND: Obesity is a major risk factor for the development of endothelial dysfunction. We explored the effect of different degrees of body mass on endothelial function, lipids, systemic inflammation and glucose homeostasis and the effect of surgically-induced weight loss on endothelial function in severely obese humans. METHODS: A cross-sectional study of healthy subjects across a wide range of body fatness was performed to characterize the effect of obesity on flow-mediated dilatation (FMD), systemic inflammation, blood pressure and insulin sensitivity. A longitudinal study was performed to assess the effect of bariatric surgery induced weight loss on these parameters. 73 healthy subjects across a wide range of body mass were recruited; of these, 8 underwent bariatric surgery (median BMI 52.2 kg/m2, interquartile range 50.355.9). Endothelial dependent vasodilatation was measured using the brachial artery vasodilatory response to forearm hyperemia assessed using highresolution ultrasonography. RESULTS: Obese subjects were characterised by a complex collection of abnormalities, with hypertension, impaired glucose homeostasis, systemic inflammation and reduced FMD. BMI < or =25 kg/m2 (median FMD 9.7%, interquartile range 6.8-12.2), BMI >30 kg/m2 (median FMD 6.7% 4.8-7.5), P=0.01 comparing FMD in lean and obese subjects. A mean reduction in weight of 23.4 (4.6) kg produced an improvement in FMD from 5.3% (3.87.0) to 10.2% (7.6-13.3), P=0.01. CONCLUSIONS: Even moderate obesity leads to endothelial dysfunction. In severely obese subjects, FMD is normalized by weight loss. This improvement in FMD is associated with a decline in inflammatory markers, blood pressure and insulin. The improvement in FMD occurred despite patients remaining significantly obese. These results suggest that an integrated approach to improving endothelial function in obese humans may be necessary.

Short-term oral folic acid supplementation enhances endothelial function in patients with type 2 diabetes.

BACKGROUND: Endothelial dysfunction and arterial stiffening are commonly observed in type 2 diabetes. These abnormalities might be secondary to increased plasma concentrations of homocysteine. We sought to determine whether oral folic acid supplementation, by lowering homocysteine levels, enhanced endothelial function and reduced arterial stiffness in type 2 diabetes. METHODS: Twenty-six type 2 diabetic patients (age 56.5 +/- 0.9 years, diabetes duration 5.5 +/- 0.6 years, means +/- SEM) with no history of cardiovascular disease received 5 mg/d of oral folic acid or placebo for 4 weeks in a double-blind, randomized controlled, parallel group trial. The following parameters were measured before and after treatment: 1) endothelial function (forearm arterial blood flow during local intra-arterial administration of endothelium-dependent [acetylcholine 1.5, 4.5, and 15 microg/min] and endothelium-independent [sodium nitroprusside 1, 2, and 4 microg/min] vasodilators); and 2) carotid-radial and carotid-femoral pulse wave velocity. RESULTS: Folic acid reduced plasma homocysteine concentrations and enhanced endothelium-dependent vasodilatation during each acetylcholine infusion rate (mean and 95% confidence interval post versus pretreatment differences in forearm arterial blood flow ratio between the infused and control arm +0.19 (0.03-0.35), P < .01; +0.39 (0.02-0.81), P < .05; and +0.40 (0.09-0.89), P < .05, respectively). Endothelium-independent vasodilatation and pulse wave velocity were not affected. No significant changes in forearm arterial blood flow and pulse wave velocity were observed in the placebo group. Multiple regression analysis showed that changes in folic acid, but not homocysteine, concentrations independently described changes in maximal endothelium-dependent vasodilatation. CONCLUSIONS: Short-term oral folic acid supplementation significantly enhances endothelial function in type 2 diabetic patients, independent of homocysteine lowering.

The clinical relevance of raised cardiac troponin I in the absence of significant angiographic coronary artery disease.

OBJECTIVES: Cardiac troponins are highly sensitive and specific markers of myocardial cell injury. We wished to determine the clinical relevance of raised troponins in the absence of significant angiographic coronary artery disease. DESIGN AND METHODS: We assessed patients admitted to our hospital over the past 3 years with troponin-positive chest pain and no angiographically significant coronary disease. RESULTS: The study included 67 patients, all of whom had symptoms of "chest pain" and elevated (>0.2 microg/L) troponin I on admission. Thirty-four (51%) patients had alternative causes for myocyte injury other than coronary ischaemia. In the remaining 33 (49%) patients we could find no other associated features or diagnoses. Follow up was obtained in 29 (88%) of these 33 patients (mean follow up 58+/-13 weeks, range 17-156 weeks). During the follow up period, three (4.5%) patients were readmitted with further ischaemic events. CONCLUSIONS: Myocardial damage can occur in the absence of significant angiographic coronary disease and other causes of raised troponins should be considered according to the clinical presentation. Troponin-positive cases with angiographically "normal" coronary arteries can re-present with future cardiac events and should still be considered for aggressive risk management.

Folic acid: a marker of endothelial function in type 2 diabetes?

OBJECTIVES: Endothelial dysfunction is a common feature of type 2 diabetes. Recent studies suggest that the B-vitamin folic acid exerts direct beneficial effects on endothelial function, beyond the well known homocysteine lowering effects. Therefore, folic acid might represent a novel "biomarker" of endothelial function. We sought to determine whether plasma levels of folic acid determine endothelial-dependent vasodilation in patients with type 2 diabetes. METHODS: Forearm arterial blood flow (FABF) was measured at baseline and during intra-brachial infusion of the endothelial-dependent vasodilator acetylcholine (15 microg/min) and the endothelial-independent vasodilator sodium nitroprusside (2 microg/min) in 26 type 2 diabetic patients (age 56.5 +/- 0.9 years, means +/- SEM) with no history of cardiovascular disease. RESULTS: FABF ratio (ie, the ratio between the infused and control forearm FABF) significantly increased during acetylcholine (1.10 +/- 0.04 vs 1.52 +/- 0.07, p < 0.001) and sodium nitroprusside (1.12 +/- 0.11 vs 1.62 +/- 0.06, p < 0.001) infusions. After correcting for age, gender, diabetes duration, smoking, hypertension, body mass index, microalbuminuria, glycated hemoglobin, low-density lipoprotein cholesterol, and homocysteine, multiple regression analysis showed that plasma folic acid concentration was the only independent determinant (p = 0.037, R2 = 0.22) of acetylcholine-mediated, but not sodium nitroprusside-mediated, vasodilatation. CONCLUSIONS: Folic acid plasma concentrations determine endothelium-mediated vasodilatation in patients with type 2 diabetes. These results support the hypothesis of a direct effect of folic acid on endothelial function and the rationale for interventions aimed at increasing folic acid levels to reduce cardiovascular risk.

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.

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.

Isoenzyme characterization in isolated elevation of alkaline phosphatase after liver transplantation in children.

BACKGROUND: Isolated transient elevation of alkaline phosphatase (ALP) in the absence of bone or liver disease has been reported in children including liver transplant patients. Specific isoenzyme patterns have been associated with this phenomenon in healthy children but have not been reported after liver transplantation. The discovery of the isoenzyme pattern associated with benign transient hyperphosphatasemia in one child prompted a study of all our posttransplant patients. METHODS: Retrospective analysis of ALP isoenzymes by polyacrylamide gel electrophoresis on banked serum samples. RESULTS: The incidence of isolated transient hyperphosphatasemia was 4.3%. All 11 children demonstrated the isoenzyme pattern associated with benign transient hyperphosphatasemia. In one child, the hyperphosphatasemia occurred on a background of chronic cholangiopathy and in a second, shortly after an episode of probable cytomegalovirus hepatitis. CONCLUSIONS: Isolated elevation of serum ALP after liver transplantation in children is common. Analysis of ALP isoenzymes, looking for the pattern of benign transient hyperphosphatasemia, can assist in the management of these children.

Effects of folic acid supplementation on inflammatory and thrombogenic markers in chronic smokers. A randomised controlled trial.

INTRODUCTION: Cigarette smoking may induce pro-inflammatory and pro-thrombotic changes. It is not known whether these abnormalities are caused at least partly by increased homocysteine levels. We investigated whether lowering homocysteine by folic acid supplementation might reduce the plasma concentration of inflammatory and thrombogenic markers in chronic smokers. MATERIAL AND METHODS: Twenty-four healthy cigarette smokers (age 37.8+/-2.5 years, mean+/-SEM) were randomly assigned to 4 weeks of folic acid 5 mg/day or placebo. The following parameters were measured before and after treatment: (1) markers of inflammation (C-reactive protein, CRP, and white cell count, WCC); (2) blood coagulation screen (Activated Partial Thromboplastin time Ratio, APTR, and International Normalized Ratio, INR); (3) pro-thrombotic markers (fibrinogen, factor VIII coagulant activity, VIII:C, von Willebrand factor, vWF, and D-dimer). RESULTS: Folic acid induced a significant reduction in homocysteine (10.8+/-0.6 vs. 8.2+/-0.5 micromol/l, p<0.001), plasma fibrinogen (3.15+/-0.14 vs. 2.87+/-0.14 g/l, p<0.05), and D-dimer (102+/-44 vs. 80+/-26 microg/l, p<0.05) concentrations. By contrast, no significant changes were observed in CRP (2.2+/-0.7 vs. 1.7+/-0.7 mg/l), WCC (7.2+/-0.5 vs. 6.8+/-0.5 10(9) cells/l), APTR (0.91+/-0.02 vs. 0.93+/-0.02), INR (0.92+/-0.01 vs. 0.91+/-0.01), vWF (103+/-8 vs. 102+/-9 U/dl), and VIII:C (120+/-8 vs. 107+/-8 U/dl) levels. Changes in folic acid plasma concentrations were significantly and negatively correlated with changes in fibrinogen (r=-0.48, p=0.01) but not with changes in D-dimer (r=-0.15, p=0.5) levels. Changes in plasma homocysteine concentrations did not correlate with changes in either fibrinogen or D-dimer. No significant changes in homocysteine, inflammatory and thrombogenic markers were observed in the placebo group. CONCLUSIONS: Short-term folic acid supplementation had no significant effects on inflammatory markers but induced a significant reduction in plasma fibrinogen and D-dimer concentrations in healthy chronic smokers. Thus, folic acid might have an anti-thrombotic effect in this high-risk group independent of the homocysteine lowering effect.

Cardiac troponin T and I and creatine kinase-MB as markers of myocardial injury and predictors of outcome following percutaneous coronary intervention.

AIMS: This study was performed to determine the most sensitive biochemical marker for the detection of cardiac myocyte damage potentially sustained during percutaneous coronary intervention (PCI) and to assess whether such a marker can be used to identify patients at increased risk of poor subsequent clinical outcome. METHODS AND RESULTS: We studied 109 consecutive patients presenting with clinical stable and unstable angina and undergoing PCI at our institution. Blood was sampled for creatine kinase-MB (CK-MB), cardiac Troponin T (cTnT) and I (cTnI) immediately before and at 6, 14 and 24 h post-PCI. Five patients with raised cardiac markers pre-PCI were excluded from further analysis. The occurrence of major adverse cardiac events (MACE) was documented in-hospital, at 30 days and at long-term clinical follow up of up to 20 months. MACE occurred in 26/109 (24%) patients: death=1, QWMI=4, NQWMI=5, repeat PCI=16 (nine target vessel revascularisations and seven de-novo lesions), CABG=5. cTnI had the highest detection rate for myocardial damage, with 58 cTnI-positive patients, 38 cTnT-positive patients and 28 CK-MB-positive patients in the 24 h following PCI (Pearson's Chi square test, P<0.01). The type of interventional strategy per se was not significantly associated with post-procedural cardiac marker concentrations (Kruskal-Wallis ANOVA, P>0.05). There was a significant association between post-procedural cardiac marker concentrations of CK-MB, cTnT and cTnI and the occurrence of procedural angiographic complications (P=0.0003, 0.0002, 0.001, respectively). All three markers, at each sampling time point between 6 and 24 h post-PCI, showed a significant predictive relationship with MACE in-hospital and at long-term follow up (ROC curve AUC analysis, P<0.05). All three markers provided equally predictive information at each of the three post-procedural sampling time points between 6 and 24 h following PCI. All levels of cardiac marker elevation above the clinically discriminant cut-off values were significantly predictive of outcome at long-term follow up. CONCLUSIONS: cTnI proved to be the most sensitive marker in detecting myocardial necrosis following PCI. CK-MB, cTnT and cTnI all provided similarly reliable prognostic information, with cTnT and cTnI being marginally superior in predicting MACE at follow up.