Circulating levels of copeptin predict outcome in patients with pulmonary arterial hypertension

Objective

To determine the levels of circulating copeptin in patients with pulmonary arterial hypertension (PAH), and to evaluate its relation with disease severity, outcome and response to treatment.

Background

Vasopressin is a key regulator of body fluid homeostasis. The co-secreted protein copeptin serves as surrogate for plasma vasopressin levels and increases in acute and chronic left ventricular dysfunction. Copeptin has not been studied in PAH.

Methods

Serum copeptin levels were evaluated in a retrospective cohort of 92 treatment-naïve patients with PAH, 39 patients with normal right ventricular hemodynamics (diseased controls) and 14 apparently healthy individuals (healthy controls). In a second prospective cohort of 15 patients with PAH, serial changes of copeptin levels after initiation of PAH treatment were measured. Copeptin levels were compared with clinical, biochemical and hemodynamic parameters as well as response to treatment and clinical outcome.

Results

Circulating copeptin levels were elevated in PAH patients compared to diseased controls (20.1 pmol/l vs. 5.1 pmol/l; p = 0.001). Baseline levels of copeptin correlated with NYHA functional class (r = 0.46; p = 0.01), 6 minute walking distance (r = -0.26; p = 0.04), NT-proBNP (r = 0.49, p = 0.01), creatinine (r = 0.39, p = 0.01) and estimated glomerular filtration rate (r = -0.32, p = 0.01). Copeptin levels did not correlate with hemodynamics but decreased after initiation of PAH therapy (p = 0.001). Elevated copeptin levels were associated with shorter survival (p < 0.001) and independent predictors of mortality in a multiple Cox regression analysis (HR1.4; 95% confidence interval 1.1-2.0; p = 0.02).

Conclusions

Patients with PAH had elevated copeptin levels. High circulating levels of copeptin were independent predictors of poor outcome, which makes copeptin a potentially useful biomarker in PAH.     

Baseline MELD Score Predicts Hepatic Decompensation during Antiviral Therapy in Patients with Chronic Hepatitis C and Advanced Cirrhosis

Background and Aims

In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined.

Methods

In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks).

Results

Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001).

Conclusions

Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.     

Altered Osteocyte-Specific Protein Expression in Bone after Childhood Solid Organ Transplantation

Background

Bone fragility is common post solid organ transplantation but little is known about bone pathology on a tissue level. Abnormal osteocytic protein expression has been linked to compromised bone health in chronic kidney disease (CKD) and immunosuppressant medications may impact osteocyte function.

Methods

Transiliac bone biopsies were obtained from 22 pediatric solid organ allograft recipients (average age 15.6 years) an average of 6.3 ± 1.2 years after transplantation and from 12 pediatric pre-dialysis CKD patients (average age 13.2 years). Histomorphometry and immunohistochemistry for FGF23, DMP1, sclerostin, and osteopontin were performed on all biopsies.

Results

FGF23 and sclerostin were increased in transplant recipients relative to non-transplant CKD, regardless of the type of allograft received and despite, in the case of liver and heart recipients, a higher GFR. Bone DMP1 expression was higher in liver or heart than in kidney recipients, concomitant with higher serum phosphate values. Osteopontin expression was higher in CKD than in transplant recipients (p<0.01). Bone FGF23 and sclerostin correlated directly (r = 0.38, p<0.05); bone FGF23 expression and osteoid thickness correlated inversely (r = - 0.46, p<0.01).

Conclusions

Solid-organ transplantation is associated with increased FGF23 and sclerostin expression. The contribution of these findings to compromised bone health post transplantation warrants further evaluation.     

Serum Sphingolipid Variations Associate with Hepatic Decompensation and Survival in Patients with Cirrhosis

Background

Sphingolipids constitute bioactive molecules with functional implications in liver homeostasis. Particularly, ablation of very long chain ceramides in a knockout mouse model has been shown to cause a severe hepatopathy.

Methods

We aimed to evaluate the serum sphingolipid profile of 244 patients with cirrhosis prospectively followed for a median period of 228±217 days via mass spectrometry.

Results

We thereby observed a significant decrease of long and very long chain ceramides, particularly of C24ceramide, in patients with increasing severity of cirrhosis (p<0.001). Additionally, hydropic decompensation, defined by clinical presentation of ascites formation, was significantly correlated to low C24ceramide levels (p<0.001) while a significant association to hepatic decompensation and poor overall survival was observed for low serum concentrations of C24ceramide (p<0.001) as well. Multivariate analysis further identified low serum C24ceramide to be independently associated to overall survival (standard beta = -0.001, p = 0.022).

Conclusions

In our current analysis serum levels of very long chain ceramides show a significant reciprocal correlation to disease severity and hepatic decompensation and are independently associated with overall survival in patients with cirrhosis. Serum sphingolipid metabolites and particularly C24ceramide may constitute novel molecular targets of disease severity, hepatic decompensation and overall prognosis in cirrhosis and should be further evaluated in basic research studies.     

The Impact of Liver Cell Injury on Health-Related Quality of Life in Patients with Chronic Liver Disease

Background

Patients with chronic liver disease often suffer from unspecific symptoms and report severe impairment in the quality of life. The underlying mechanisms are multifactorial and include disease-specific but also liver related causes. The current analysis evaluated the association of hepatocellular apoptosis in non-viral chronic liver disease and health-related quality of life (HRQL). Furthermore we examined factors, which influence patient''s physical and mental well-being.

Methods

A total of 150 patients with non-infectious chronic liver disease were included between January 2014 and June 2015. The German version of the Chronic Liver Disease Questionnaire (CLDQ-D), a liver disease specific instrument to assess HRQL, was employed. Hepatocellular apoptosis was determined by measuring Cytokeratin 18 (CK18, M30 Apoptosense ELISA).

Results

Female gender (5.24 vs. 5.54, p = 0.04), diabetes mellitus type II (4.75 vs. 5.46, p<0.001) and daily drug intake (5.24 vs. 6.01, p = 0.003) were associated with a significant impairment in HRQL. HRQL was not significantly different between the examined liver diseases. Levels of CK18 were the highest in patients with NASH compared to all other disease entities (p<0.001). Interestingly, CK18 exhibited significant correlations with obesity (p<0.001) and hyperlipidemia (p<0.001). In patients with cirrhosis levels of CK18 correlated with the MELD score (r = 0.18, p = 0.03) and were significantly higher compared to patients without existing cirrhosis (265.5 U/l vs. 186.9U/l, p = 0.047). Additionally, CK18 showed a significant correlation with the presence and the degree of hepatic fibrosis (p = 0.003) and inflammation (p<0.001) in liver histology. Finally, there was a small negative association between CLDQ and CK18 (r = -0.16, p = 0.048).

Conclusion

Different parameters are influencing HRQL and CK18 levels in chronic non-viral liver disease and the amount of hepatocellular apoptosis correlates with the impairment in HRQL in chronic non-viral liver diseases. These findings support the role of liver-protective therapies for the improvement of the quality of life in chronic liver disease.     

Alterations in Cerebral White Matter and Neuropsychology in Patients with Cirrhosis and Falls

Background & Aim

Falls are frequent in patients with cirrhosis but underlying mechanisms are unknown. The aim was to determine the neuropsychological, neurological and brain alterations using magnetic resonance-diffusion tensor imaging (MR-DTI) in cirrhotic patients with falls.

Patients and methods

Twelve patients with cirrhosis and falls in the previous year were compared to 9 cirrhotic patients without falls. A comprehensive neuropsychological and neurological evaluation of variables that may predispose to falls included: the Mini-Mental State Examination, Psychometric Hepatic Encephalopathy Score (PHES), Parkinson’s Disease-Cognitive Rating Scale, specific tests to explore various cognitive domains, Unified Parkinson’s Disease Rating Scale to evaluate parkinsonism, scales for ataxia and muscular strength, and electroneurography. High-field MR (3T) including DTI and structural sequences was performed in all patients.

Results

The main neuropsychological findings were impairment in PHES (p = 0.03), Parkinson’s Disease-Cognitive Rating Scale (p = 0.04) and in executive (p<0.05) and visuospatial-visuoconstructive functions (p<0.05) in patients with falls compared to those without. There were no statistical differences between the two groups in the neurological evaluation or in the visual assessment of MRI. MR-DTI showed alterations in white matter integrity in patients with falls compared to those without falls (p<0.05), with local maxima in the superior longitudinal fasciculus and corticospinal tract. These alterations were independent of PHES as a covariate and correlated with executive dysfunction (p<0.05).

Conclusions

With the limitation of the small sample size, our results suggest that patients with cirrhosis and falls present alterations in brain white matter tracts related to executive dysfunction. These alterations are independent of PHES impairment.     

Copeptin Levels Remain Unchanged during the Menstrual Cycle

Background

Copeptin, a surrogate marker for arginin vasopressin production, is evaluated as an osmo-dependent stress and inflammatory biomarker in different diseases. We investigated copeptin during the menstrual cycle and its relationship to sex hormones, markers of subclinical inflammation and estimates of body fluid.

Methods

In 15 healthy women with regular menstrual cycles, blood was drawn on fifteen defined days of their menstrual cycle and was assayed for copeptin, progesterone, estradiol, luteinizing hormone, high-sensitive C-reactive protein, tumor necrosis factor-alpha and procalcitonin. Symptoms of fluid retention were assessed on each visit, and bio impedance analysis was measured thrice to estimate body fluid changes. Mixed linear model analysis was performed to assess the changes of copeptin across the menstrual cycle and the relationship of sex hormones, markers of subclinical inflammation and estimates of body fluid with copeptin.

Results

Copeptin levels did not significantly change during the menstrual cycle (p = 0.16). Throughout the menstrual cycle, changes in estradiol (p = 0.002) and in the physical premenstrual symptom score (p = 0.01) were positively related to copeptin, but changes in other sex hormones, in markers of subclinical inflammation or in bio impedance analysis-estimated body fluid were not (all p = ns).

Conclusion

Although changes in estradiol and the physical premenstrual symptom score appear to be related to copeptin changes, copeptin does not significantly change during the menstrual cycle.     

Serum Autotaxin Is a Parameter for the Severity of Liver Cirrhosis and Overall Survival in Patients with Liver Cirrhosis – A Prospective Cohort Study

Background

Autotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients.

Methods

Patients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry.

Results

270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, P<0.001). Serum ATX levels correlated with the Child-Pugh stage and the MELD (model of end stage liver disease) score and LPA levels (r = 0.493, P = 0.027). Patients with hepatic encephalopathy (P = 0.006), esophageal varices (P = 0.002) and portal hypertensive gastropathy (P = 0.008) had higher ATX levels than patients without these complications. Low ATX levels were a parameter independently associated with longer overall survival (hazard ratio 0.575, 95% confidence interval 0.365–0.905, P = 0.017).

Conclusion

Serum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients.     

Concentrations of the Stress Hormone Copeptin Increase upon Hypoglycaemia in Patients with Type 1 Diabetes Dependent of Hypoglycaemia Awareness

Objective

Copeptin, a marker for stress mirroring vasopressin concentrations, has been shown to increase upon insulin-induced hypoglycaemia in patients after transsphenoidal surgery of pituitary adenomas. Patients with type 1 diabetes mellitus are prone to hypoglycaemia, but no data about copeptin levels upon hypoglycaemia are available. Furthermore, the perception of hypoglycaemia can vary from total unawareness to disabling episodes. The aim of this study was to investigate whether copeptin increases upon hypoglycaemia in patients with type 1 diabetes mellitus and is associated with the degree of hypoglycaemia awareness.

Materials and Methods

In this prospective observational study, 17 patients with type 1 diabetes underwent a standardized insulin infusion test. Blood sampling for glucose and copeptin was performed at baseline and after 60 minutes (min). To assess hypoglycaemia associated symptoms the Mood and Symptom Questionnaire (MSQ) was conducted at baseline and after 60 min.

Results

During insulin infusion, blood glucose decreased from 5.1 (SD±0.2) to 3.0 (±0.5) mmol/L at 60 min (p<0.001). Copeptin concentrations increased from 3.2 (±1.7) to 3.8 (±1.9) pmol/L (p = 0.03). Mood and Symptoms Questionnaire scores increased from 14 (±3.0) to 18 (±5.8), (p = 0.006). Patients with good hypoglycaemia awareness had an increase in copeptin from 3.0 (±1.8) to 4.2 (±2.4) pmol/L (p = 0.03) in contrast to patients more unaware of hypoglycaemia who only showed an increase in copeptin from 3.3 (±1.6) to 3.6 (±1.4) pmol/L (p = 0.4). There was a trend to a larger copeptin increase in patients aware of hypoglycemia compared to patients unaware of hypoglycemia (p = 0.074).

Conclusion

Copeptin increases in patients with type 1 diabetes upon insulin induced hypoglycaemia. Interestingly, the copeptin increase seems associated with the degree of hypoglycaemia awareness. This hypothesis warrants further verification.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00515801","term_id":"NCT00515801"}}NCT00515801     

Renal Function Interferes with Copeptin in Prediction of Major Adverse Cardiac Events in Patients Undergoing Vascular Surgery

Objective

Precise perioperative risk stratification is important in vascular surgery patients who are at high risk for major adverse cardiovascular events (MACE) peri- and postoperatively. In clinical practice, the patient’s perioperative risk is predicted by various indicators, e.g. revised cardiac index (RCRI) or modifications thereof. Patients suffering from chronic kidney disease (CKD) are stratified into a higher risk category. We hypothesized that Copeptin as a novel biomarker for hemodynamic stress could help to improve the prediction of perioperative cardiovascular events in patients undergoing vascular surgery including patients with chronic kidney disease.

Methods

477 consecutive patients undergoing abdominal aortic, peripheral arterial or carotid surgery from June 2007 to October 2012 were prospectively enrolled. Primary endpoint was 30-day postoperative major adverse cardiovascular events (MACE).

Results

41 patients reached the primary endpoint, including 63.4% aortic, 26.8% carotid, and 9.8% peripheral surgeries. Linear regression analysis showed that RCRI (P< .001), pre- (P< .001), postoperative Copeptin (P< .001) and Copeptin level change (P= .001) were associated with perioperative MACE, but CKD remained independently associated with MACE and Copeptin levels. Multivariate regression showed that increased Copeptin levels added risk predictive information to the RCRI (P= .003). Especially in the intermediate RCRI categories was Copeptin significantly associated with the occurrence of MACE. (P< .05 Kruskal Wallis test). Subdivision of the study cohort into CKD stages revealed that preoperative Copeptin was significantly associated with CKD stages (P< .0001) and preoperative Copeptin measurements could not predict MACE in patients with more severe CKD stages.

Conclusion

Preoperative Copeptin loses its risk predictive potential for perioperative MACE in patients with chronic kidney disease undergoing vascular surgery.     

Adipose Tissue Dysfunction and Altered Systemic Amino Acid Metabolism Are Associated with Non-Alcoholic Fatty Liver Disease

Background

Fatty liver is a major cause of obesity-related morbidity and mortality. The aim of this study was to identify early metabolic alterations associated with liver fat accumulation in 50- to 55-year-old men (n = 49) and women (n = 52) with and without NAFLD.

Methods

Hepatic fat content was measured using proton magnetic resonance spectroscopy (¹H MRS). Serum samples were analyzed using a nuclear magnetic resonance (NMR) metabolomics platform. Global gene expression profiles of adipose tissues and skeletal muscle were analyzed using Affymetrix microarrays and quantitative PCR. Muscle protein expression was analyzed by Western blot.

Results

Increased branched-chain amino acid (BCAA), aromatic amino acid (AAA) and orosomucoid were associated with liver fat accumulation already in its early stage, independent of sex, obesity or insulin resistance (p<0.05 for all). Significant down-regulation of BCAA catabolism and fatty acid and energy metabolism was observed in the adipose tissue of the NAFLD group (p<0.001for all), whereas no aberrant gene expression in the skeletal muscle was found. Reduced BCAA catabolic activity was inversely associated with serum BCAA and liver fat content (p<0.05 for all).

Conclusions

Liver fat accumulation, already in its early stage, is associated with increased serum branched-chain and aromatic amino acids. The observed associations of decreased BCAA catabolism activity, mitochondrial energy metabolism and serum BCAA concentration with liver fat content suggest that adipose tissue dysfunction may have a key role in the systemic nature of NAFLD pathogenesis.     

Effortless Attention as a Biomarker for Experienced Mindfulness Practitioners

Objective

The present study aimed at comparing frontal beta power between long-term (LTM) and first-time meditators (FTM), before, during and after a meditation session. We hypothesized that LTM would present lower beta power than FTM due to lower effort of attention and awareness.

Methods

Twenty one participants were recruited, eleven of whom were long-term meditators. The subjects were asked to rest for 4 minutes before and after open monitoring (OM) meditation (40 minutes).

Results

The two-way ANOVA revealed an interaction between the group and moment factors for the Fp1 (p<0.01), F7 (p = 0.01), F3 (p<0.01), Fz (p<0.01), F4 (p<0.01), F8 (p<0.01) electrodes.

Conclusion

We found low power frontal beta activity for LTM during the task and this may be associated with the fact that OM is related to bottom-up pathways that are not present in FTM.

Significance

We hypothesized that the frontal beta power pattern may be a biomarker for LTM. It may also be related to improving an attentive state and to the efficiency of cognitive functions, as well as to the long-term experience with meditation (i.e., life-time experience and frequency of practice).     

Lung Transplantation for Lymphangioleiomyomatosis in Japan

Background

Lung transplantation has been established as the definitive treatment option for patients with advanced lymphangioleiomyomatosis (LAM). However, the prognosis after registration and the circumstances of lung transplantation with sirolimus therapy have never been reported.

Methods

In this national survey, we analyzed data from 98 LAM patients registered for lung transplantation in the Japan Organ Transplantation Network.

Results

Transplantation was performed in 57 patients as of March 2014. Survival rate was 86.7% at 1 year, 82.5% at 3 years, 73.7% at 5 years, and 73.7% at 10 years. Of the 98 patients, 21 had an inactive status and received sirolimus more frequently than those with an active history (67% vs. 5%, p<0.001). Nine of twelve patients who remained inactive as of March 2014 initiated sirolimus before or while on a waiting list, and remained on sirolimus thereafter. Although the statistical analysis showed no statistically significant difference, the survival rate after registration tended to be better for lung transplant recipients than for those who awaited transplantation (p = 0.053).

Conclusions

Lung transplantation is a satisfactory therapeutic option for advanced LAM, but the circumstances for pre-transplantation LAM patients are likely to alter with the use of sirolimus.     

Serum Level of Soluble Receptor for Advanced Glycation End Products Is Associated with A Disintegrin And Metalloproteinase 10 in Type 1 Diabetes

Background

The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of diabetic complications, and soluble forms of the receptor (sRAGE) can counteract the detrimental action of the full-length receptor by acting as decoy. Soluble RAGE is produced by alternative splicing [endogenous secretory RAGE (esRAGE)] and/or by proteolytic cleavage of the membrane-bound receptor. We have investigated the role of A Disintegrin And Metalloproteinase 10 (ADAM10) in the ectodomain shedding of RAGE.

Methods

Constitutive and insulin-induced shedding of RAGE in THP-1 macrophages by ADAM10 was evaluated using an ADAM10-specific metalloproteinase inhibitor. Serum ADAM10 level was measured in type 1 diabetes and control subjects, and the association with serum soluble RAGE was determined. Serum total sRAGE and esRAGE were assayed by ELISA and the difference between total sRAGE and esRAGE gave an estimated measure of soluble RAGE formed by cleavage (cRAGE).

Results

RAGE shedding (constitutive and insulin-induced) was significantly reduced after inhibition of ADAM10 in macrophages, and insulin stimulated ADAM10 expression and activity. Diabetic subjects have higher serum total sRAGE and esRAGE (p<0.01) than controls, and serum ADAM10 was also increased (p<0.01). Serum ADAM10 correlated with serum cRAGE in type 1 diabetes (r = 0.40, p<0.01) and in controls (r = 0.31. p<0.01) but no correlations were seen with esRAGE. The association remained significant after adjusting for age, gender, BMI, smoking status and HbA1c.

Conclusion

Our data suggested that ADAM10 contributed to the shedding of RAGE. Serum ADAM10 level was increased in type 1 diabetes and was a significant determinant of circulating cRAGE.     

Effects of a 12-Week Hatha Yoga Intervention on Metabolic Risk and Quality of Life in Hong Kong Chinese Adults with and without Metabolic Syndrome

Objective

To determine the efficacy of a 12-week Hatha yoga intervention to improve metabolic risk profiles and health-related quality of life (HRQoL) in Chinese adults with and without metabolic syndrome (MetS).

Methods

We conducted a controlled trial within an university-affiliated hospital. 173 Chinese men and women aged 18 or above were assigned to either the yoga intervention group (n = 87) or the control group (n = 86). Primary outcomes included 12-week change in metabolic risk factors and MetS z score. Secondary outcome was HRQoL (Medical Outcomes Short Form Survey at 12 weeks).

Results

The mean age of participants was 52.0 (SD 7.4, range 31-71) years. Analysis involving the entire study population revealed that the yoga group achieved greater decline in waist circumference (p<0.001), fasting glucose (p<0.01), triglycerides (p<0.05), and MetS z score (p<0.01). Yoga training also improved general health perceptions (p<0.01), physical component score (p<0.01), and social functioning (p<0.01) domains score of HRQoL. However, no significant differences between groups were observed in the mean change of systolic/diastolic blood pressures or high-density lipid protein cholesterol (all p>0.05). There were no significant differences in the intervention effects on waist circumference and MetS z score between the MetS subgroups (both p>0.05).

Conclusion

A 12-week Hatha yoga intervention improves metabolic risk profiles and HRQoL in Chinese adults with and without MetS.

Trial Registration

Australian New Zealand Clinical Trials Registry ACTRN12613000816752     

Copeptin as a Serum Biomarker of Febrile Seizures

Background and Objectives

Accurate diagnosis of febrile seizures in children presenting after paroxysmal episodes associated with fever, is hampered by the lack of objective postictal biomarkers. The aim of our study was to investigate whether FS are associated with increased levels of serum copeptin, a robust marker of arginine vasopressin secretion.

Methods

This was a prospective emergency-setting cross-sectional study of 161 children between six months and five years of age. Of these, 83 were diagnosed with febrile seizures, 69 had a febrile infection without seizures and nine had epileptic seizures not triggered by infection. Serum copeptin and prolactin levels were measured in addition to standard clinical, neurophysiological, and laboratory assessment. Clinical Trial Registration: NCT01884766.

Results

Circulating copeptin was significantly higher in children with febrile seizures (median [interquartile range] 18.9 pmol/L [8.5-36.6]) compared to febrile controls (5.6 pmol/L [4.1-9.4]; p <0.001), with no differences between febrile and epileptic seizures (21.4 pmol/L [16.1-46.6]; p = 0.728). In a multivariable regression model, seizures were the major determinant of serum copeptin (beta 0.509; p <0.001), independently of clinical and baseline laboratory indices. The area under the receiver operating curve for copeptin was 0.824 (95% CI 0.753-0.881), significantly higher compared to prolactin (0.667 [0.585-0.742]; p <0.001). The diagnostic accuracy of copeptin increased with decreasing time elapsed since the convulsive event (at 120 min: 0.879 [0.806-0.932] and at <60 min: 0.975 [0.913-0.997]).

Conclusions

Circulating copeptin has high diagnostic accuracy in febrile seizures and may be a useful adjunct for accurately diagnosing postictal states in the emergency setting.     

Young People’s Preferences for Family Planning Service Providers in Rural Malawi: A Discrete Choice Experiment

Objective

To quantify the impact of service provider characteristics on young people’s choice of family planning (FP) service provider in rural Malawi in order to identify strategies for increasing access and uptake of FP among youth.

Methods and Findings

A discrete choice experiment was developed to assess the relative impact of service characteristics on preferences for FP service providers among young people (aged 15–24). Four alternative providers were included (government facility, private facility, outreach and community based distribution of FP) and described by six attributes (the distance between participants’ home and the service delivery point, frequency of service delivery, waiting time at the facility, service providers’ attitude, availability of FP commodities and price). A random parameters logit model was used to estimate preferences for service providers and the likely uptake of services following the expansion of outreach and community based distribution (CBDA) services. In the choice experiment young people were twice as likely to choose a friendly provider (government service odds ratio [OR] = 2.45, p<0.01; private service OR = 1.99, p<0.01; CBDA OR = 1.88, p<0.01) and more than two to three times more likely to choose a provider with an adequate supply of FP commodities (government service OR = 2.48, p<0.01; private service OR = 2.33, p<0.01; CBDA = 3.85, p<0.01). Uptake of community based services was greater than facility based services across a variety of simulated service scenarios indicating that such services may be an effective means of expanding access for youth in rural areas and an important tool for increasing service uptake among youth.

Conclusions

Ensuring that services are acceptable to young people may require additional training for service providers in order to ensure that all providers are friendly and non-judgemental when dealing with younger clients and to ensure that supplies are consistently available.     

Effects of Antiepileptic Drug Monotherapy on One-Carbon Metabolism and DNA Methylation in Patients with Epilepsy

Purpose

The aim of this study was to compare the serum levels of one-carbon metabolism (OCM) nutrients (e.g., folate, homocysteine and vitamin B12) and peripheral blood DNA methylation in epileptic patients under treatment with antiepileptic drugs (AEDs) and in healthy controls.

Methods

In this cross-sectional study, 60 patients with epilepsy who were receiving valproate (VPA) (n = 30) or lamotrigine (LTG) (n = 30) monotherapy were enrolled. Thirty age and sex matched healthy subjects served as the controls. Serum concentrations of OCM nutrients and peripheral blood DNA methylation status were measured.

Results

Compared to the control group, the VPA group had higher serum levels of homocysteine (p<0.05). No difference in homocysteine concentration was observed in the LTG group. Patients receiving VPA or LTG had significantly lower serum folate levels in comparison with controls (p<0.001). The level of methylation of long interspersed nucleotide element-1 (LINE-1) in peripheral blood was not significantly different between the AED monotherapy group and healthy controls. A difference in the methylation levels of methylenetetrahydrofolate reductase (MTHFR) amplicon was observed between AED-treated patients with epilepsy and controls (p<0.01). A positive correlation between serum folate levels and peripheral blood MTHFR amplicon methylation status was also observed (r = 0.25, p = 0.023).

Conclusion

Our findings suggest that the effects of AED monotherapy on OCM may induce specific regions of DNA hypomethylation.     

Autologous Bone Marrow Mononuclear Cell Transplantation in Patients with Decompensated Alcoholic Liver Disease: A Randomized Controlled Trial

Objective

Impaired liver regeneration is associated with a poor outcome in patients with decompensated alcoholic liver disease (ALD). We assessed whether autologous bone marrow mononuclear cell transplantation (BMMCT) improved liver function in decompensated ALD.

Design

58 patients (mean age 54 yrs; mean MELD score 19, all with cirrhosis, 81% with alcoholic steatohepatitis at baseline liver biopsy) were randomized early after hospital admission to standard medical therapy (SMT) alone (n = 30), including steroids in patients with a Maddrey’s score ≥32, or combined with G-CSF injections and autologous BMMCT into the hepatic artery (n = 28). Bone marrow cells were harvested, isolated and reinfused the same day. The primary endpoint was a ≥3 points decrease in the MELD score at 3 months, corresponding to a clinically relevant improvement in liver function. Liver biopsy was repeated at week 4 to assess changes in Ki67+/CK7+ hepatic progenitor cells (HPC) compartment.

Results

Both study groups were comparable at baseline. After 3 months, 2 and 4 patients died in the BMMCT and SMT groups, respectively. Adverse events were equally distributed between groups. Moderate alcohol relapse occurred in 31% of patients. The MELD score improved in parallel in both groups during follow-up with 18 patients (64%) from the BMMCT group and 18 patients (53%) from the SMT group reaching the primary endpoint (p = 0.43 (OR 1.6, CI 0.49–5.4) in an intention to treat analysis. Comparing liver biopsy at 4 weeks to baseline, steatosis improved (p<0.001), and proliferating HPC tended to decrease in both groups (−35 and −33%, respectively).

Conclusion

Autologous BMMCT, compared to SMT is a safe procedure but did not result in an expanded HPC compartment or improved liver function. These data suggest either insufficient regenerative stimulation after BMMCT or resistance to liver regenerative drive in patients with decompensated alcoholic cirrhosis.

Trial Registration

Controlled-Trials.com ISRCTN83972743.     

Circulating microRNA-200 Family as Diagnostic Marker in Hepatocellular Carcinoma

Goals

In this clinical study, we aimed to evaluate the role of circulating microRNA-200 family as a non-invasive tool to identify patients with cirrhosis-associated hepatocellular carcinoma (HCC).

Background

Prognosis of HCC remains poor with increasing incidence worldwide, mainly related to liver cirrhosis. So far, no reliable molecular targets exist for early detection of HCC at surgically manageable stages. Recently, we identified members of the microRNA-200 family as potential diagnostic markers of cirrhosis-associated HCC in patient tissue samples. Their value as circulating biomarkers for HCC remained undefined.

Methods

Blood samples and clinicopathological data of consecutive patients with liver diseases were collected prospectively. Expression of the microRNA-200 family was investigated by qRT-PCR in blood serum samples of 22 HCC patients with and without cirrhosis. Serum samples of patients with non-cancerous chronic liver cirrhosis (n = 22) and of healthy volunteers (n = 15) served as controls.

Results

MicroRNA-141 and microRNA-200a were significantly downregulated in blood serum of patients with HCC compared to liver cirrhosis (p<0.007) and healthy controls (p<0.002). MicroRNA-141 and microRNA-200a could well discriminate patients with cirrhosis-associated HCC from healthy volunteers with area under the receiver-operating characteristic curve (AUC) values of 0.85 and 0.82, respectively. Additionally, both microRNAs could differentiate between HCC and non-cancerous liver cirrhosis with a fair accuracy.

Conclusions

Circulating microRNA-200 family members are significantly deregulated in patients with HCC and liver cirrhosis. Further studies are necessary to confirm the diagnostic value of the microRNA-200 family as accurate serum marker for cirrhosis-associated HCC.