Diagnoses and mortality in a population without acute myocardial infarction, but with elevated high-sensitive troponin I - a retrospective register-based single center study.

AIM: To explore, which differential diagnoses to consider in individuals with elevated troponins without acute myocardial infarction (AMI), and the mortality for those individuals. METHODS: Retrospective, register-based study on a representative sample of the Danish population with the following inclusion criteria: High-sensitive troponin I (hs-TnI) ⋝25 ng/L, age ⋝18 years, and exclusion of AMI. RESULTS: 3067 individuals without AMI but increased hs-TnI were included. Most frequent discharge diagnoses: Pneumonia (12.8%), Aortic valve disorder (11.3%), Medical observation (10.9%) and Heart failure (8.9%). The 30-days and one-year mortality was 15.8% and 32.0%, respectively. CONCLUSIONS: A selected number of alternative diagnoses must be considered in individuals with increased hs-TnI. Due to high mortality it is crucial to carefully evaluate these individuals despite the absence of AMI.

Patient knowledge of anticoagulant treatment does not correlate with treatment quality.

OBJECTIVES: The objectives of this study were to investigate whether patient knowledge is a predictor of treatment stability in anticoagulant clinic patients and to evaluate the correlation between the patients' subjective assessment of own knowledge and their score on a validated knowledge assessment instrument. STUDY DESIGN: This is a prospective study where international normalized ratio (INR) stability was followed up 6 months after knowledge assessment. METHODS: We analyzed data of 42 consecutive patients new to vitamin-K antagonist (VKA) treatment and 64 experienced patients from an anticoagulant clinic offering patient education. The patients filled out a VKA knowledge assessment questionnaire with 24 items under standardized conditions, and simultaneously, they were asked about their subjective knowledge. Subsequently, time in range of INR (TIR) was collected for each patient. RESULTS: Out of the 106 patients, 52 had 18 or more correct answers (>75%), defined as a 'satisfactory level' of objective knowledge. The average TIR was 73%, and treatment stability was significantly higher in experienced patients than new patients. We found no correlation between objective knowledge and TIR (Spearman rho = -0.03, P = 0.78). Most patients (77%) reported a high subjective knowledge of VKA, but no correlation was found between objective and subjective knowledge (Spearman rho = 0.129, P = 0.19). CONCLUSION: We observed that many patients had a low level of knowledge of VKA, despite high treatment stability and patient education. The patient's own assessment of knowledge was not found to predict objective knowledge, which could have implications for selection of patients for self-test or self-management of treatment.

Congenital Chloride Diarrhea: Diagnosis by Easy-Accessible Chloride Measurement in Feces.

Background. Congenital chloride diarrhea (CCD) is an autosomal recessive disorder caused by mutations in the genes encoding the intestinal Cl(-)/HCO3 (-) exchanger and is clinically characterized by watery, profound diarrhea, electrolyte disturbances, and metabolic alkalosis. The CCD diagnosis is based on the clinical symptoms and measurement of high chloride concentration in feces (>90 mmol/L) and is confirmed by DNA testing. Untreated CCD is lethal, while long-term clinical outcome improves when treated correctly. Case Presentation. A 27-year-old woman had an emergency caesarian due to pain and discomfort in gestational week 36 + 4. The newborn boy had abdominal distension and yellow fluid per rectum. Therapy with intravenous glucose and sodium chloride decreased his stool frequency and improved his clinical condition. A suspicion of congenital chloride diarrhea was strongly supported using blood gas analyzer to measure an increased chloride concentration in the feces; the diagnosis was confirmed by DNA testing. Discussion. Measurement of chloride in feces using an ordinary blood gas analyzer can serve as a preliminary analysis when congenital chloride diarrhea is suspected. This measurement can be easily performed with a watery feces composition. An easy-accessible chloride measurement available will facilitate the diagnostics and support the initial treatment if CCD is suspected.

Platelet count is associated with cardiovascular disease, cancer and mortality: A population-based cohort study.

INTRODUCTION: Platelet count is used to determine bleeding risk and monitoring thrombopoiesis. While abnormal platelet counts are associated with mortality and morbidity, it is unclear whether it also apply to platelet counts within reference range. We investigated the relationship between platelet count (100-450×109/L) and mortality, development of future cardiovascular disease (myocardial infarction, ischaemic stroke, or peripheral vascular disease), venous thromboembolism, bleeding or cancer in the general population. MATERIAL AND METHODS: We conducted a register-based cohort study of 21,252 adults (≥20years) from the Danish General Suburban Population Study (GESUS). Laboratory results from GESUS were linked to information from national registers regarding morbidity and death. Cox proportional hazard regression was conducted with adjustment for age, sex, smoking status, haemoglobin, leukocyte count, C-reactive protein and Charlson comorbidity index. RESULTS: We found a U-shaped relationship between mortality and platelet count. Mortality was significantly increased for platelet count <175×109/L or >300×109/L. When categorizing platelet count using the interval 201-250×109/L as reference group, platelet count 301-450×109/L was associated with mortality, adjusted hazard ratio (HR)=1.42(95% CI 1.06-1.90) and cardiovascular disease, adjusted HR=1.32 (95% CI 1.03-1.69). Platelet count 100-200×109/L was associated with future cancer, adjusted HR=1.28(95% CI 1.05-1.57), but not with future bleeding or venous thromboembolism. CONCLUSIONS: Platelet count is associated with mortality, future cardiovascular disease, and future cancer.

Single test isolated lupus anticoagulant positivity is associated with increased plasma levels of inflammatory markers and dyslipidemia.

OBJECTIVE: To investigate whether a single positive test for lupus anticoagulant (LA) is associated with levels of inflammatory markers and traditional cardiovascular risk factors, independent of autoimmune disease, thrombophilia and occurrence of other antiphospholipid antibodies. METHODS: In a retrospective observational study we included persons referred for thrombophilia testing during 2011-2014. Persons with autoimmune disease, thrombophilia or presence of specific anti-phospholipid antibodies were excluded. Multivariate logistic regression analyses adjusted for age and sex was performed and odds ratios (ORs) with 95% confidence intervals (95% CI) calculated. RESULTS: Of 381 individuals tested, 271 fulfilled the criteria, of whom 22 (8%) were LA positive and 249 (92%) LA negative. LA positivity was associated with higher body mass index (BMI) (OR 1.12, 95% CI: 1.03-1.23, p = 0.01); C-reactive protein (OR 1.08 95% CI:1.04-1.11, p < 0.001); fibrinogen (OR 1.51 95% CI: 1.27-1.78, p < 0.001); coagulation factor VIII (FVIII) (OR 1.73 95% CI: 1.01-2.96, p = 0.046), low high density lipoprotein (HDL) (OR 0.03 95% CI: 0.00-0.19, p < 0.001) and high triglyceride (OR 1.81 95% CI: 1.12-2.92, p = 0.02) compared with LA negative individuals. CONCLUSION: This study shows that single test isolated LA positivity is associated with increased levels of inflammatory markers, low HDL cholesterol, elevated triglyceride and high BMI.

Standardization of collection requirements for fasting samples: for the Working Group on Preanalytical Phase (WG-PA) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM).

Standardized protocols for patient preparation for laboratory testing are currently lacking. Moreover, a great heterogeneity exists in the definitions of "fasting" currently being used among healthcare workers and in the literature. Marked metabolic and hormonal changes occur after food ingestion, mainly due to the absorption of fluids, lipids, proteins, carbohydrates and other food constituents. This postprandial response varies markedly in response to numerous factors, such as eating behavior, food composition, fasting duration, time of the day, chronic and acute smoking, coffee and alcohol consumption. It is therefore crucial to minimize the total variability by controlling as many of these modifying factors as possible. Control of the abovementioned effects on postprandial response can only be achieved by standardizing the way patients are prepared for laboratory testing, i.e. by defining the fasting duration, as well as what is and what is not allowed (e.g., coffee, tea, smoking, water) during the period of fasting prior to sample collection. The aim of this article is to describe the range of effects of different approaches to fasting on laboratory tests, and to provide a framework for the harmonization of definitions for fasting requirements for laboratory tests.

The relationship between HbA1c and fasting plasma glucose in patients with increased plasma liver enzyme measurements.

BACKGROUND: HbA(1c) is currently being introduced for diagnostic purpose in diabetes. Previous studies have, however, indicated that patients with liver disease have false low HbA(1c) levels. We therefore investigated the correlation between HbA(1c) and plasma glucose in patients with different levels of increased liver enzyme concentrations. METHODS: Data from 10,065 patients with simultaneous measurement of HbA(1c), venous fasting plasma glucose, alanine aminotransferase and γ-glutamyl transferase were extracted from our laboratory database. Correlations were investigated in four patient groups divided according to their liver enzyme concentrations. RESULTS: The correlation between HbA(1c) and plasma glucose was high in all groups, with r = 0.77 for men and r = 0.78 for women (P < 0.001), a correlation confirmed with multiple regression analysis (P < 0.001). However, interaction analysis revealed that linear regression lines were significantly different for men and women, with increase of both liver enzyme measurements and also, for women, with increased alanine aminotransferase. When compared with biological variation for HbA(1c), only men with increased measurements of both liver enzymes had a clinically important decrease in HbA(1c). CONCLUSIONS: Increased liver enzyme concentrations do not bias the correlation between HbA(1c) and fasting plasma glucose. However, men with low plasma glucose and increased concentrations of both liver enzymes do have a slightly decreased HbA(1c) and, if the clinical suspicion is strong enough, one should consider supplement testing.

Intrauterine extremity gangrene and cerebral infarction at term: a case report.

Intrauterine extremity gangrene in combination with cerebral infarction is a serious and rare event. We present a case with a healthy mother who gave birth to a child with this condition. At term, the mother presented at the antenatal clinic with decreased fetal movements. Cardiotocography (CTG) showed signs of fetal distress and a caesarean section was performed. The left arm of the newborn was found gangrenous. Amputation of the arm was necessary and the child was subsequently treated with anticoagulant therapy due to thrombosis and cerebral infarction in the left hemisphere found by magnetic resonance imaging (MRI). At one year of age the boy was doing well and had prosthesis as a left arm. He had no signs of further complications. Despite thorough examination of the parents and the child, the reason for the thrombosis is still unknown.

Plasma osteoprotegerin concentrations in peripheral sensory neuropathy in Type 1 and Type 2 diabetic patients.

AIMS: Osteoprotegerin (OPG) has been linked to different diabetes complications, including cardiovascular disease, and new findings have indicated a specific role in diabetic peripheral neuropathy, but the exact mechanism is unknown. To investigate a possible association between OPG and diabetic peripheral sensory neuropathy, we therefore analysed plasma OPG in Type 1 and Type 2 diabetic patients with and without peripheral neuropathy. SUBJECTS AND METHODS: Two hundred Type 1 diabetes mellitus (T1DM) patients and 305 Type 2 diabetes mellitus (T2DM) patients participated in the study. Plasma OPG was measured with a sandwich immunoassay. Peripheral neuropathy was assessed by the Semmes-Weinstein monofilament test. RESULTS: In T2DM, plasma OPG concentrations were significantly higher in the peripheral neuropathy group (P < 0.001). Furthermore, there was a significant relationship between the presence of neuropathy in T2DM and plasma OPG levels on logistic regression (P = 0.006). However, when investigated in a full multiple regression model including other long-term diabetes complications, the association became insignificant (P = 0.092). In T1DM, the difference in plasma OPG between groups did not reach significance (P = 0.066). However, plasma OPG significantly correlated to peripheral neuropathy in this group also (P = 0.022), although this correlation was not significant in a multiple linear regression model (P = 0.051). CONCLUSION: Plasma OPG levels are related to peripheral neuropathy in both Type 1 and Type 2 diabetes, although with the strongest relationship in T2DM. Before understanding the significance of this, the pathological mechanism involved and, speculatively, a possible use of plasma OPG as a peripheral sensory neuropathy marker, a larger prospective study is needed.

High-sensitive C-reactive protein is associated with reduced lung function in young adults.

Systemic inflammation has been associated with reduced lung function. However, data on the interrelationships between lung function and inflammation are sparse, and it is not clear if low-grade inflammation leads to reduced lung function. Associations between high-sensitive C-reactive protein (CRP) and spirometric lung function were assessed in a population-based cohort of approximately 1,000 Danes aged 20 yrs. In males, the average decline in forced expiratory volume in one second (FEV(1)) in the highest CRP quintile was 23 mL.yr(-1) versus 1.6 mL.yr(-1) in the lowest quintile. In females, the average decline was 6.2 mL.yr(-1) in the highest CRP quintile versus an increase of 1.8 mL.yr(-1) in the lowest CRP quintile. In a multiple regression analysis adjusted for sex, body mass index, cardiorespiratory fitness, smoking, asthma, airway hyperresponsiveness and serum eosinophil cationic protein, higher levels of CRP at age 20 yrs were associated with a greater reduction in both FEV(1) and forced vital capacity between ages 20 and 29 yrs. The findings show that higher levels of C-reactive protein in young adults are associated with subsequent decline in lung function, suggesting that low-grade systemic inflammation in young adulthood may lead to impaired lung function independently of the effects of smoking, obesity, cardiorespiratory fitness, asthma and eosinophilic inflammation.

The influence of anaemia on stroke prognosis and its relation to N-terminal pro-brain natriuretic peptide.

Anaemia is a negative prognostic factor for patients with heart failure and impaired renal function, but its role in stroke patients is unknown. Furthermore, anaemia has been shown to influence the level of N-terminal pro-brain natriuretic peptide (NT-proBNP), but this is only investigated in patients with heart failure, not in stroke patients. Two-hundred-and-fifty consecutive, well-defined ischemic stroke patients were investigated. Mortality was recorded at 6 months follow-up. Anaemia was diagnosed in 37 patients (15%) in whom stroke severity was worse than in the non-anaemic group, whilst the prevalence of renal affection, smoking and heart failure was lower. At 6 months follow-up, 23 patients were dead, and anaemia had an odds ratio of 4.7 when adjusted for age, Scandinavian Stroke Scale and a combined variable of heart and/or renal failure and/or elevation of troponin T using logistic regression. The median NT-proBNP level in the anaemic group was significantly higher than in the non-anaemic group, and in a multivariate linear regression model, anaemia remained an independent predictor of NT-proBNP. Conclusively, anaemia was found to be a negative prognostic factor for ischemic stroke patients. Furthermore, anaemia influenced the NT-proBNP level in ischemic stroke patients, an important aspect when interpreting NT-proBNP in these patients.

Localization of human serum amyloid P component and heparan sulfate proteoglycan in in vitro-formed Abeta fibrils.

Ultrastructural studies of the localization of serum amyloid P component (SAP) in amyloid fibrils have given divergent results. We here report for the first time that electron microscopy of SAP coincubated with Abeta1-42 peptides or with mature Abeta1-42 fibrils, revealed SAP molecules coating the surface of the mature fibrils and that protofibrils of Abeta1-42 did not bind SAP. Also when incubated with extracted amyloid light chain (AL)-fibrils the SAP molecules aligned on the fibril surface. Heparan sulfate proteoglycan bound to the surface of the Abeta fibrils with a spacing of about 50 nm. We conclude that SAP does not bind to protofibrils but to the surface of mature Abeta fibrils and that it may stabilize and protect the fibrils.

Complement activation by the amyloid proteins A beta peptide and beta 2-microglobulin.

Complement activation (CA) has been reported to play a role in the pathogenesis of Alzheimer's disease (AD). To investigate whether CA may contribute to amyloidogenesis in general, the CA potential of different amyloid fibril proteins was tested. CA induced by A beta preparations containing soluble protein, protofilaments and some fibrils or only fibrils in a solid phase system (ELISA) was modest with a slow kinetics compared to the positive delta IgG control. Soluble A beta induced no detectable CA in a liquid phase system (complement consumption assay) while fibrillar A beta caused CA at 200 mg/ml and higher concentrations. Soluble beta 2-microglobulin (beta 2M) purified from peritoneal dialysates was found to be as potent a complement activator as A beta in both solid and liquid phase systems while beta 2M purified from urine exhibited lower activity, a difference which may be explained by differences observed in SDS-resistant oligomers and isoforms. Soluble Amyloid A-protein caused no significant CA. A beta and beta 2M activated complement via the classical pathway. The modifying influence by amyloid-associated molecules on A beta-induced CA was also investigated, but neither serum amyloid P component nor heparan sulfate did significantly alter the A beta-induced CA. The results indicate that not only fibrillar A beta but also oligomers of, in particular, beta 2M from patients with dialysis-associated amyloidosis are capable of inducing CA at supra-physiological concentrations.

An ultrastructural study of amyloid intermediates in A beta1-42 fibrillogenesis.

Many attempts have been made to define early stages and intermediates in amyloid fibrillogenesis that may be susceptible to inhibition. We have developed an in vitro system, based on the use of A beta1-42 peptides, in which the development of prestages of protofilaments and protofilament and fibril formation could, for the first time, be followed by electron microscopy, supported by fluorescence spectrometry. The first recognizable ultrastructures after incubation of A beta1-42 peptides at 37 degrees C were globular subunits (4-5 nm in diameter) that gradually became organized into short protofilaments (30-100 nm), which in turn formed fibrils mainly by lateral association. At this stage, part of the protofilaments were seen first as collaterals protruding from the fibrils and then, as they were gradually incorporated, as buds on the fibril surface. A continuous growth of A beta1-42 fibrils was observed, seemingly originating from a nucleus, which appeared to consist of aggregates of amyloid intermediates. That protofilaments are intermediates also in the in vivo formation of amyloid was supported by the finding that AL fibrils isolated from amyloid tissues also exhibited radiating protofilaments. The demonstrated globular subunits and early formed protofilaments may be attractive targets for inhibition of fibril formation.

Isoforms of murine and human serum amyloid P component.

Isoelectric focusing (IEF) and immunofixation of murine serum amyloid P component (SAP), purified and in serum, showed a distinct and strain-dependent isoform pattern with up to seven bands (pI 5.1-5.7). Neuraminidase treatment caused a shift of the isoforms to more basic pI values, but did not affect their number. When the acute-phase response was analysed in three mouse strains, CBA/J and C3H/HeN initially showed seven SAP isoforms in serum and C57BL/6 J three or four. The responses in all three strains peaked at day 2 and were normalized within 14 days. On days 2 and 4, CBA/J and C3H/HeN mice showed one more acidic isoform and an increase in the concentration of the most basic isoform. C57BL/6 J mice exhibited two to three new isoforms during the acute-phase response. This appears to be the first demonstration of the physiological existence of SAP isoforms. In contrast, demonstration of isoforms of human SAP required the presence of urea and higher SAP concentrations. TEF and immunofixation of SAP monomers showed five to eight isoforms, ranging from pI 4.7-5.7. IEF of SAP in human serum resulted in a less distinct pattern and more acidic isoforms. As with murine SAP, neuraminidase treatment caused a shift of the isoforms, but no reduction in isoform number. Two-dimensional gel electrophoresis confirmed the existence of multiple isoforms of human SAP monomers.

Increased plasma concentration of serum amyloid P component in centenarians with impaired cognitive performance.

Serum amyloid P component (SAP) binds to all amyloid fibrils including those in the plaques and tangles of Alzheimer patients. To investigate whether the plasma SAP concentration correlated to cognitive impairment, we measured SAP levels in blood samples from 41 centenarians and compared these to the cognitive performance evaluated by Mini Mental State Examination (MMSE). We observed a significantly (p < 0.001) increased SAP concentration (48.3+/-16.9 microg/ml; mean +/- SD) in the centenarians compared to gender-matched controls (32.8+/-11.4 microg/ml). Six severely demented centenarians had an even higher SAP concentration (60.2 microg/ml), while the subgroup of cognitive intact centenarians (MMSE score >24) showed a normal SAP concentration (38.4+/-9.3 microg/ml). No dehydration or hepatic dysfunction was demonstrable in the centenarians. We conclude that the centenarians with impaired cognitive performance had significantly increased plasma concentrations of SAP, while the values for cognitive intact centenarians were within the normal range.

Reduced expression of C5a receptors on neutrophils from cord blood.

AIM: To describe further functional deficiencies of neonatal neutrophils by measuring the expression of C5a receptors. METHODS: C5a uptake was measured using flow cytometry with fluorescein isothiocynate labelled recombinant C5a. The response of neutrophils to stimulation with C5a and fMLP was tested by measuring migration and exocytosis of myeloperoxidase and lactoferrin. RESULTS: C5a mean fluorescence on neutrophils from neonates was significantly lower (22.4 (SD 3.5)) than in adult controls (31.5 (3.1)). Neutrophils from neonates migrated poorly towards both C5a and fMLP compared with those from adult controls. Exocytosis of myeloperoxidase, but not lactoferrin from neonatal neutrophils stimulated with C5a, was significantly lower than in adult controls. fMLP stimulation, on the other hand, resulted in significantly higher exocytosis in neonates. CONCLUSION: The lower expression of C5a receptors on neutrophils from neonates could be related to reduced C5a mediated exocytosis of myeloperoxidase.