New pediatric percentiles of liver enzyme serum levels (alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase): Effects of age, sex, body mass index, and pubertal stage.

The present study aims to clarify the effects of sex, age, body mass index (BMI), and puberty on transaminase serum levels in children and adolescents and to provide new age- and sex-related percentiles for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyltransferase (GGT). Venous blood and anthropometric data were collected from 4,126 cases. Excluded were cases of participants with potential hepatotoxic medication, with evidence of potential illness at the time of blood sampling and non-normal BMI (BMI <10th or >90th). The resulting data (N = 3,131 cases) were used for the calculations of ALT, AST, and GGT percentiles. Age- and sex-related reference intervals were established by using an LMS method of Cole-type method. Serum levels of transaminases follow age-specific patterns and relate to the onset of puberty. This observation is more pronounced in girls than in boys. ALT percentiles showed similar-shaped patterns in both sexes. Multivariate regression confirmed significant effects of puberty and BMI-SDS (ß = 2.21) on ALT. Surprisingly, AST serum levels were negatively influenced by age (ß = -1.42) and BMI-SDS (ß = -0.15). GGT percentiles revealed significant sex-specific differences, correlated positively with age (ß = 0.37) and showed significant association with BMI-SDS (ß = 1.16). CONCLUSION: Current reference values of ALT, AST, and GGT serum levels were calculated for children between 11 months and 16.0 years, using modern analytical and statistical methods. This study extends the current knowledge about transaminases by revealing influences of age, sex, BMI, and puberty on serum concentrations of all three parameters and has for these parameters one of the largest sample sizes published so far. (Hepatology 2017).

Fas/CD95 regulatory protein Faim2 is neuroprotective after transient brain ischemia.

Death receptor (DR) signaling has a major impact on the outcome of numerous neurological diseases, including ischemic stroke. DRs mediate not only cell death signals, but also proinflammatory responses and cell proliferation. Identification of regulatory proteins that control the switch between apoptotic and alternative DR signaling opens new therapeutic opportunities. Fas apoptotic inhibitory molecule 2 (Faim2) is an evolutionary conserved, neuron-specific inhibitor of Fas/CD95-mediated apoptosis. To investigate its role during development and in disease models, we generated Faim2-deficient mice. The ubiquitous null mutation displayed a viable and fertile phenotype without overt deficiencies. However, lack of Faim2 caused an increase in susceptibility to combined oxygen-glucose deprivation in primary neurons in vitro as well as in caspase-associated cell death, stroke volume, and neurological impairment after cerebral ischemia in vivo. These processes were rescued by lentiviral Faim2 gene transfer. In summary, we provide evidence that Faim2 is a novel neuroprotective molecule in the context of cerebral ischemia.

A Combined Clinical and Serum Biomarker-Based Approach May Allow Early Differentiation Between Patients With Minor Stroke and Transient Ischemic Attack as Well as Mid-term Prognostication.

Background: Early differentiation between transient ischemic attack (TIA) and minor ischemic stroke (MIS) impacts on the patient's individual diagnostic work-up and treatment. Furthermore, estimations regarding persisting impairments after MIS are essential to guide rehabilitation programs. This study evaluated a combined clinical- and serum biomarker-based approach for the differentiation between TIA and MIS as well as the mid-term prognostication of the functional outcome, which is applicable within the first 24 h after symptom onset. Methods: Prospectively collected data were used for a retrospective analysis including the neurological deficit at admission (National Institutes of Health Stroke Scale, NIHSS) and the following serum biomarkers covering different pathophysiological aspects of stroke: Coagulation (fibrinogen, antithrombin), inflammation (C reactive protein), neuronal damage in the cellular [neuron specific enolase], and the extracellular compartment [matrix metalloproteinase-9, hyaluronic acid]. Further, cerebral magnetic resonance imaging was performed at baseline and day 7, while functional outcome was evaluated with the modified Rankin Scale (mRS) after 3, 6, and 12 months. Results: Based on data from 96 patients (age 64 ± 14 years), 23 TIA patients (NIHSS 0.6 ± 1.1) were compared with 73 MIS patients (NIHSS 2.4 ± 2.0). In a binary logistic regression analysis, the combination of NIHSS and serum biomarkers differentiated MIS from TIA with a sensitivity of 91.8% and a specificity of 60.9% [area under the curve (AUC) 0.84]. In patients with NIHSS 0 at admission, this panel resulted in a still acceptable sensitivity of 81.3% (specificity 71.4%, AUC 0.69) for the differentiation between MIS (n = 16) and TIA (n = 14). By adding age, remarkable sensitivities of 98.4, 100, and 98.2% for the prediction of an excellent outcome (mRS 0 or 1) were achieved with respect to time points investigated within the 1-year follow-up. However, the specificity was moderate and decreased over time (83.3, 70, 58.3%; AUC 0.96, 0.92, 0.91). Conclusion: This pilot study provides evidence that the NIHSS combined with selected serum biomarkers covering pathophysiological aspects of stroke may represent a useful tool to differentiate between MIS and TIA within 24 h after symptom onset. Further, this approach may accurately predict the mid-term outcome in minor stroke patients, which might help to allocate rehabilitative resources.

Spontaneous cervical artery dissection is accompanied by a hypercoagulable state and simultaneous inflammatory condition.

BACKGROUND: Spontaneous cervical artery dissections (sCAD) are often preceded by infections. However, existing data about inflammatory parameters remained inconsistent. Remarkably, concurrent information about the coagulation system, whose affection seems also reasonable to cause ischaemic events, are still lacking in sCAD patients. Thus, this study explores the association between the inflammatory and coagulation system in patients with sCAD. METHODS: The parameters leukocyte and thrombocyte count, C-reactive protein, fibrinogen, D-dimer, activated partial thromboplastin time (aPTT) and prothrombin time were extracted from hospital-based medical records of patients (n = 60) with sCAD and compared with those of a control group (n = 97) from a prospective observational stroke study. Univariate analyses were added by multiple regression analyses. RESULTS: As compared with the control group, patients with sCAD had an increased leucocyte count (9.2 ± 3.2 vs. 7.9 ± 2.2 × 109/l; p = 0.003), an increased thrombocyte count (252 ± 52 vs. 229 ± 64 × 109/l; p = 0.021), a shortened aPTT 28.0 ± 3.5 vs. 29.9 ± 3.6 s; p = 0.001) and decreased D-dimer values (0.44 ± 0.29 vs. 0.76 ± 0.73 mg/l; p = 0.002). However, in multiple regression analyses adjusted for age, sex, initial stroke severity, arterial hypertension, diabetes mellitus and smoking only the shortened aPTT remained statistically significant (p = 0.045) between groups, while differences on leucocyte count (p = 0.087), thrombocyte count (p = 0.234) and D-dimer (p = 0.321) failed statistical significance. CONCLUSION: We found evidence for a hypercoagulable state in patients with sCAD as indicated by a shortened aPTT, which was associated with a trend to an increased leucocyte count at the same time. Our findings first strengthen the hypothesis that inflammation critically impacts on the occurrence of sCAD, and second linked this condition with a marked affection of the coagulation system.

Does physiological distribution of blood parameters in children depend on socioeconomic status? Results of a German cross-sectional study.

OBJECTIVES: In the present study, we examined the relation between socioeconomic status (SES) and the physiological distribution of iron-related blood parameters. DESIGN: This is a cross-sectional analysis of longitudinal population-based cohort study. SETTING: Based on a sample of healthy participants from a German research centre, various blood parameters and values of clinical examinations and questionnaires were collected. PARTICIPANTS: A total of 1206 healthy volunteers aged 2.5 to 19 years, one child per family randomly selected, were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Associations between the SES of children by Winkler-Stolzenberg Index (WSI) and its dimensions (income, education, occupation) and iron-related blood parameters (haemoglobin, ferritin and transferrin) were analysed by linear regression analyses. Gender and pubertal stage were included as covariables. Additionally, associations between SES of children by WSI and physical activity (side-to-side jumps, push-ups) as well as body mass index (BMI) were analysed by linear regression analyses. RESULTS: Children with high WSI or family income showed significantly increased z-scores for haemoglobin (P=0.046; P<0.001). Children with increased WSI or family income showed significantly lower z-scores for transferrin (P<0.001). There was a significant correlation between haemoglobin and gender (P<0.001) and between transferrin and pubertal stage (P=0.024). Furthermore, physical activity was positively correlated and BMI was negatively correlated with WSI (P<0.001). DISCUSSION: Our data show an association between SES and the distribution of iron-dependent parameters. Lower SES is correlated with lower values for haemoglobin and higher values for transferrin. Furthermore, we demonstrate that physical activity and BMI are associated with SES. Whereas higher SES is correlated with higher values for physical activity and lower BMI. Our parameters are standardised as z-scores with the advantages that the results are comparable across different age groups and present physiological courses. TRIAL REGISTRATION NUMBER: NCT02550236; Results.

Beyond soluble transferrin receptor: old challenges and new horizons.

Disturbances of iron metabolism are a frequent challenge in outpatient and inpatient care. Although several established biomarkers are commonly used by clinicians for differential diagnosis, the discrimination between latent or classic iron deficiency, anaemia of chronic disease or a combination of functional iron deficiency (iron-restricted erythropoiesis) with anaemia of chronic disease in patients affected by inflammatory disease can be demanding. Soluble transferrin receptor (sTfR) is a cleaved monomer of transferrin receptor 1 and correlates positively with tissue iron deficiency as well as with stimulated erythropoiesis. The ratio between sTfR and ferritin in combination with reticulocyte haemoglobin content further helps to identify different states of iron deficiency. In this review, we will focus on biological aspects of iron metabolism and sTfR, established clinical applications and limitations of sTfR and derived indices, and prospects of future research and applications.

Modulation of hippocampal neuroplasticity by Fas/CD95 regulatory protein 2 (Faim2) in the course of bacterial meningitis.

Fas-apoptotic inhibitory molecule 2 (Faim2) is a neuron-specific membrane protein and a member of the evolutionary conserved lifeguard apoptosis regulatory gene family. Its neuroprotective effect in acute neurological diseases has been demonstrated in an in vivo model of focal cerebral ischemia. Here we show that Faim2 is physiologically expressed in the human brain with a changing pattern in cases of infectious meningoencephalitis.In Faim2-deficient mice, there was increased caspase-associated hippocampal apoptotic cell death and an increased extracellular signal-regulated kinase pattern during acute bacterial meningitis induced by subarachnoid infection with Streptococcus pneumoniae type 3 strain. However, after rescuing the animals by antibiotic treatment, Faim2 deficiency led to increased hippocampal neurogenesis at 7 weeks after infection. This was associated with improved performance of Faim2-deficient mice compared to wild-type littermates in the Morris water maze, a paradigm for hippocampal spatial learning and memory. Thus, Faim2 deficiency aggravated degenerative processes in the acute phase but induced regenerative processes in the repair phase of a mouse model of pneumococcal meningitis. Hence, time-dependent modulation of neuroplasticity by Faim2 may offer a new therapeutic approach for reducing hippocampal neuronal cell death and improving cognitive deficits after bacterial meningitis.