Thomas Wiesel

Infection of T lymphocytes in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children of non-Asian origin.

Epstein‐Barr virus (EBV) is one of the most frequent triggers of hemophagocytic lymphohistiocytosis (HLH). EBV‐associated HLH (EBV‐HLH) and ectopic infection of T cells has been particularly described in patients from Far East Asia.

Pain in pediatric oncology — children's and parents' perspectives

There is a lack of valid epidemiological data on malignancy‐associated pain in modern pediatric oncology. Pediatric oncology patients (self‐assessment) and their parents from 28 hospitals were questioned using age‐adapted, structured interviews and validated pain assessment tools. Pain intensity was measured by the NRS and Bieri faces scale. We conducted 363 interviews with patients and their parents, and 46 with the parents alone (if patients <2.5 years). Pain was reported at the time of the interview or within the last 24 h, 7 d, or 4 weeks in 15%, 28%, 50% and 58% of cases, respectively. The proportion of patients suffering severe to maximal pain (NRS > 3; Bieri > 2) increased significantly (p = 0.001, χ2 test). The median pain intensity for the most severe pain episode within the last 4 weeks was 6.7 (NRS 0–10). Adverse effects of anti‐tumor therapy were the most frequent cause of pain. Multivariate analyses depicted general physical condition either “severely reduced” (ASA status 3) (OR 4.0, 95% CI 1.1‐14.7, p = 0.037) or “moderately reduced” (ASA status 2) (OR 1.8, 95% CI 1.1‐2.9, p = 0.018), “in‐patient status” (OR 1.8, 95% CI 1.2‐2.9, p = 0.010), and “co‐morbidity present” (OR 3.5, 95% CI 1.1‐10.7, p = 0.030) as risk factors for severe to maximal pain. General anesthesia was the only factor significantly (OR 0.14, 95% CI 0.05‐0.39, p < 0.01) associated with a reduction in the proportion of patients suffering severe to maximal pain during bone marrow aspiration. Our data emphasize both the importance of in‐house acute pain control and the need for general anesthesia during painful procedures in pediatric oncology.

Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency

Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRαβ+CD4-CD8- double negative T cells and impaired T cell apoptosis are hallmarks of the disease. In contrast, the B cell compartment has been less well studied. We found an altered distribution of B cell subsets with raised transitional B cells and reduced marginal zone B cells, switched memory B cells and plasma blasts in most of 22 analyzed ALPS patients. Moreover, 5 out of 66 ALPS patients presented with low IgG and susceptibility to infection revealing a significant overlap between ALPS and common variable immunodeficiency (CVID). In patients presenting with lymphoproliferation, cytopenia, hypogammaglobulinemia and impaired B cell differentiation, serum biomarkers were helpful in addition to apoptosis tests for the identification of ALPS patients. Our observations may indicate a role for apoptosis defects in some diseases currently classified as CVID.

Insulin resistance in children and adolescents with type 1 diabetes mellitus: relation to obesity

Abstract:  Background:  Insulin resistance is well recognized both in type 1 diabetes mellitus (T1DM) and in obesity. Studies concerning the relation between insulin resistance and overweight in T1DM have not yet been carried out.

Coenzyme Q10 in plasma and erythrocytes: comparison of antioxidant levels in healthy probands after oral supplementation and in patients suffering from sickle cell anemia

BACKGROUND The membrane-associated antioxidant coenzyme Q10 (CoQ10) or ubiquinone-10 is frequently measured in serum or plasma. However, little is known about the total contents or redox status of CoQ10 in blood cells. METHODS We have developed a method for determination of CoQ10 in erythrocytes. Total CoQ10 in erythrocytes was compared to the amounts of ubiquinone-10 and ubihydroquinone-10 in plasma using high-pressure liquid chromatography (HPLC) with electrochemical detection and internal standardisation (ubiquinone-9, ubihydroquinone-9). RESULTS Investigations in 10 healthy probands showed that oral intake of CoQ10 (3 mg/kg/day) led to a short-term (after 5 h, 1.57+/-0.55 pmol/microl plasma) and long-term (after 14 days, 4.00+/-1.88 pmol/microl plasma, p<0.05 vs. -1 h, 1.11+/-0.24 pmol/microl plasma) increase in plasma concentrations while decreasing the redox status of CoQ10 (after 14 days, 5.37+/-1.31% in plasma, p<0.05 vs. -1 h, 6.74+/-0.86% in plasma). However, in these healthy probands, CoQ10 content in red blood cells remained unchanged despite excessive supplementation. In addition, plasma and erythrocyte concentrations of CoQ10 were measured in five patients suffering from sickle cell anemia, a genetic anemia characterised by an overall accelerated production of reactive oxygen species. While these patients showed normal or decreased plasma levels of CoQ10 with a shifting of the redox state in favour of the oxidised part (10.8-27.2% in plasma), the erythrocyte concentrations of CoQ10 were dramatically elevated (280-1,093 pmol/10(9) ERY vs. 22.20+/-6.17 pmol/10(9) ERY). CONCLUSIONS We conclude that normal red blood cells may regulate their CoQ10 content independently from environmental supplementation, but dramatic changes may be expected under pathological conditions.

Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma

Overall survival is poor in children with primary unresectable hepatocellular carcinoma. Sorafenib has been shown to significantly improve progression‐free survival in adult hepatocellular carcinoma (HCC) patients. We evaluated the experience of PLADO (cisplatin 80 mg/m2/day, doxorubicin 2 × 30 mg/m2/day) in combination with sorafenib in pediatric HCC patients.

Antioxidant level and redox status of coenzyme Q10 in the plasma and blood cells of children with diabetes mellitus type 1

Abstract:  Hyperglycaemia has been reported to cause increased production of oxygen free radicals. Oxidative stress may contribute to the pathogenesis of diabetic complications. Coenzyme Q10 (CoQ10) is known for its key role in mitochondrial bioenergetics and is considered as a potent antioxidant and free radical scavenger. This study was conducted to evaluate plasma and blood cell concentrations of CoQ10 in accordance to its redox capacity in children with diabetes mellitus type 1. CoQ10 plasma and blood cell concentrations and redox status were measured using high‐performance liquid chromatography with electrochemical detection in 43 children with diabetes mellitus type 1 and compared with 39 healthy children. In addition, the diabetic patients were subdivided according to their haemoglobin A1c (HbA1c) values into two groups, that is, those with good control (<8%) and those with poor control (>8%), and the CoQ10 status was compared between the two groups. Children with type 1 diabetes showed increased plasma levels of CoQ10 in comparison to healthy children. While CoQ10 erythrocyte and platelet concentrations did not differ, in the diabetes group, the platelet redox status differed with a significantly increased part of reduced CoQ10. This difference in concentration and redox status in comparison to healthy controls may be attributed to the subgroup of patients with poor control, as the subdivision of diabetic patients according to their HbA1c values shows. In diabetic children, especially in those with poor control, an increase in plasma concentration and intracellular redox capacity of the antioxidant CoQ10 may contribute to the body’s self‐protection during a state of enhanced oxidative stress.

Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia

Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3+TCRα/β+CD4−CD8− “double negative” T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.