Involving children and young people in clinical research through the forum of a European Young Persons’ Advisory Group: needs and challenges

Children and young people are seen as fundamental to the design and delivery of clinical research as active and reflective participants. In Europe, involvement of children and young people in clinical research is promoted extensively in order to engage young people in research as partners and to give them a voice to raise their own issues or opinions and for their involvement in planning and decision making in addition to learning research skills. Children and young people can be trained in clinical research through participation in young person advisory groups (YPAGs). Members of YPAGs assist other children and young people to learn about clinical research and share their experience and point of view with researchers, thereby possibly influencing all phases of research including the development and prioritization of research questions, design and methods, recruitment plans, and strategies for results dissemination. In the long term, the expansion of YPAGs in Europe will serve as a driving force for refining pediatric clinical research. It will help in a better definition of research projects according to the patients’ needs. Furthermore, direct engagement of children and young people in research will be favorable to both researchers and young people.     

Contraction‐induced Mmp13 and −14 expression by goat articular chondrocytes in collagen type I but not type II gels

Collagen gels are promising scaffolds to prepare an implant for cartilage repair but several parameters, such as collagen concentration and composition as well as cell density, should be carefully considered, as they are reported to affect phenotypic aspects of chondrocytes. In this study we investigated whether the presence of collagen type I or II in gel lattices affects matrix contraction and relative gene expression levels of matrix proteins, MMPs and the subsequent degradation of collagen by goat articular chondrocytes. Only floating collagen I gels, and not those attached or composed of type II collagen, contracted during a culture period of 12 days. This coincided with an upregulation of both Mmp13 and ?14 gene expression, whereas Mmp1 expression was not affected. The release of hydroxyproline in the culture medium, indicating matrix degradation, was increased five‐fold in contracted collagen I gels compared to collagen II gels without contraction. Furthermore, blocking contraction of collagen I gels by cytochalasin B inhibited Mmp13 and ?14 expression and the release of hydroxyproline. The expression of cartilage‐specific ECM genes was decreased in contracted collagen I gels, with increased numbers of cells with an elongated morphology, suggesting that matrix contraction induces dedifferentiation of chondrocytes into fibroblast‐like cells. We conclude that the collagen composition of the gels affects matrix contraction by articular chondrocytes and that matrix contraction induces an increased Mmp13 and ?14 expression as well as matrix degradation. Copyright © 2011 John Wiley & Sons, Ltd.     

Clinicopathological Features of Colon Polyps from African-Americans

Background and Aims  

Among the ethnic groups, the age-standardized incidence rate of colorectal cancer (CRC) is highest among African-Americans. The majority of CRC arise from preexisting adenoma. It is shown that 30% of the US adult population has adenomas. The potential risk of malignant transformation in adenomas differs by specific pathologic and clinical characteristics that we aimed to study in AAs.     

Daily variations in type II iodothyronine deiodinase activity in the rat brain as controlled by the biological clock

Type II deiodinase (D2) plays a key role in regulating thyroid hormone-dependent processes in, among others, the central nervous system (CNS) by accelerating the intracellular conversion of T4 into active T3. Just like the well-known daily rhythm of the hormones of the hypothalamo-pituitary-thyroid axis, D2 activity also appears to show daily variations. However, the mechanisms involved in generating these daily variations, especially in the CNS, are not known. Therefore, we decided to investigate the role the master biological clock, located in the hypothalamus, plays with respect to D2 activity in the rat CNS as well as the role of one of its main hormonal outputs, i.e. plasma corticosterone. D2 activity showed a significant daily rhythm in the pineal and pituitary gland as well as hypothalamic and cortical brain tissue, albeit with a different timing of its acrophase in the different tissues. Ablation of the biological clock abolished the daily variations of D2 activity in all four tissues studied. The main effect of the knockout of the suprachiasmatic nuclei (SCN) was a reduction of nocturnal peak levels in D2 activity. Moreover, contrary to previous observations in SCN-intact animals, in SCN-lesioned animals, the decreased levels of D2 activity are accompanied by decreased plasma levels of the thyroid hormones, suggesting that the SCN separately stimulates D2 activity as well as the hypothalamo-pituitary-thyroid axis.     

Plasma therapy in thrombotic thrombocytopenic purpura: review of the literature and the Bern experience in a subgroup of patients with severe acquired ADAMTS-13 deficiency

Based on clinical studies daily plasma exchange (PE) has become the first-choice therapy for thrombotic thrombocytopenic purpura (TTP) since 1991. Recent findings may explain its effectiveness, which particularly may include supply of ADAMTS-13 and removal of anti-ADAMTS-13 autoantibodies and unusually large von Willebrand factor (VWF) multimers. The most preferable PE regimens as well as replacement fluids are discussed and treatment-related adverse reactions are summarized. Proposals for a potential reduction of their frequency and for improvement of treatment efficiency are given. These suggestions are partially based on the experience of our institution in adult patients with severe ADAMTS-13 deficiency (<5% activity), and include (1) continuous calcium-gluconate infusion during PE in order to reduce citrate-related adverse reactions; (2) the evaluation of solvent/detergent-treated (S/D) plasma as replacement fluid in order to reduce adverse events due to fresh frozen plasma (FFP); (3) the evaluation of immunoadsorption in order to increase procedural efficiency in autoantibody removal; and (4) the substitution of ADAMTS-13 by means of recombinant drug instead of plasma.     

Severe Hyperglycemia Immediately After Allogeneic Hematopoietic Stem-Cell Transplantation is Predictive of Acute Graft-Versus-Host Disease

Stress hyperglycemia and acute graft-versus-host disease (GVHD), the major early complication of hematopoietic stem cell transplantation (HSCT), are both associated with excessive release of inflammatory cytokines. We investigated whether new-onset hyperglycemia immediately after HSCT predicts acute GVHD. We studied nondiabetic adult recipients of human leukocyte antigen-matched HSCT (peripheral blood stem cells) for acute leukemia. Using mean morning serum glucose on Days 1–10, we classified hyperglycemia as: mild (6.11–8.33 mmol/L), moderate (8.34–9.98), and severe (minimum of 9.99). Subjects who were GVHD‐free on Day 10 were followed during Days 11–100 for grades II–IV acute GVHD or competing event. Evaluation utilized cumulative incidence-based proportional hazards regression. Subjects (n?=?328) were age 18–74, median of 49 years. Per body mass index (BMI)—25.0 % were obese (BMI, 30–48), 33.8 % overweight (25 to <30), 30.8 % normal weight (21 to <25), and 10.4 % lean (18 to <21). Mild, moderate, or severe hyperglycemia occurred during Days 1–10 in 50.0, 21.3, and 16.8 % of subjects, respectively. Cumulative incidence on Day 100 was 44.8 (±2.8)?% acute GVHD and 7.9 (±1.5)?% competing event. Among normal-to-overweight subjects (n?=?212), severe hyperglycemia developed in 14.2 % (n?=?30) and more than doubled the risk of acute GVHD (hazards ratio, 2.71; 95 % CI, 1.58–4.65—adjusted for donor/recipient characteristics, prophylactic regimen, and mucositis). In contrast, among obese subjects (n?=?82), severe hyperglycemia developed in 30.5 % (n?=?25) but did not significantly affect risk of GVHD. (No lean subjects (n?=?34) developed severe hyperglycemia.) Hyperglycemia that was less than severe had an effect indistinguishable from normoglycemia. In nondiabetic patients, severe hyperglycemia immediately after allogeneic HSCT indicates increased likelihood of acute GVHD. This association is absent in obese patients, who may be primed by obesity-induced inflammation to develop severe hyperglycemia even without experiencing the cytokine storm that is essential to GVHD pathogenesis.     

Delayed Haematological recovery after autologous stem cell transplantation is associated with favourable outcome in acute myeloid leukaemia

Autologous stem cell transplantation (ASCT) is applied to consolidate first remission in patients with acute myeloid leukaemia (AML). However, outcome after ASCT widely varies among AML patients. We analyzed the prognostic significance of haematological recovery for neutrophils [absolute neutrophil count (ANC) >1·0 × 10⁹/l] and platelets (platelet count >20·0 × 10⁹/l), stratifying at day 20 after ASCT in 88 consecutive and homogeneously treated AML patients in first remission. We observed that patients with delayed recovery had better overall survival (OS; ANC: P < 0·0001 and platelets: P = 0·0062) and time to progression (TTP; ANC: P = 0·0003 and platelets: P = 0·0125). Delayed recovery was an independent marker for better OS and TTP in a multivariate analysis including age, gender, number of transfused CD34+ cells, cytogenetics, FLT3‐internal tandem duplication and NPM1 mutation. Our results suggest that delayed neutrophil and platelet recovery is associated with longer OS and TTP in AML patients consolidated with ASCT in first remission.     

Gemfibrozil Pretreatment Affecting Antioxidant Defense System and Inflammatory, but not Nrf-2 Signaling Pathways Resulted in Female Neuroprotection and Male Neurotoxicity in the Rat Models of Global Cerebral Ischemia–Reperfusion

Two important pathophysiological mechanisms involved during cerebral ischemia are oxidative stress and inflammation. In pathological conditions such as brain ischemia the ability of free radicals production is greater than that of elimination by endogenous antioxidative systems, so brain is highly injured due to oxidation and neuroinflammation. Fibrates as peroxisome proliferator-activated receptor (PPAR)-α ligands, are reported to have antioxidant and anti-inflammatory actions. In this study, gemfibrozil, a fibrate is investigated for its therapeutic potential against global cerebral ischemia–reperfusion (I/R) injury of male and female rats. This study particularly has focused on inflammatory and antioxidant signaling pathways, such as nuclear factor erythroid-related factor (Nrf)-2, as well as the activity of some endogenous antioxidant agents. It was found that pretreatment of animals with gemfibrozil prior to I/R resulted in a sexually dimorphic outcome. Within females it proved to be protective, modulating inflammatory factors and inducing antioxidant defense system including superoxide dismutase (SOD), catalase, as well as glutathione level. However, Nrf-2 signaling pathway was not affected. It also decreased malondialdehyde level as an index of lipid peroxidation. In contrast, gemfibrozil pretreatment was toxic to males, enhancing the expression of inflammatory factors such as tumor necrosis factor-α, nuclear factor-κB, and cyclooxygenase-2, and decreasing Nrf-2 expression and SOD activity, leading to hippocampal neurodegeneration. Considering that gemfibrozil is a commonly used anti-hyperlipidemic agent in clinic, undoubtedly more investigations are crucial to exactly unravel its sex-dependent neuroprotective/neurodegenerative potential.     

Synthesis of fluorene and/or benzophenone O-oxime ethers containing amino acid residues and study of their cardiovascular and antibacterial effects

The syntheses and biological studies of O-oxime ethers having α-amino acid residues as new analogs of IPS-339 have been described. In this synthesis, the reaction of fluorene and/or benzophenone O-oxime with epichlorohydrin or epibromohydrin afforded the corresponding O-oxime ether adducts. The N-alkylation of amino acid with O-oxime ether adducts led to synthesis of new analogs of IPS-339. The products were examined for their cardiovascular property. It was demonstrated that 2-(3-(9H-fluoren-9-ylideneaminooxy)-2-hydroxypropylamino)-3-methyl-butanoic acid as the most potent compound substantially reduces the heart rate of dogs. Compounds were also evaluated for their in vitro antibacterial activity against some Gram-negative and Gram-positive bacteria. The antibacterial screening proved the considerable antibacterial activity against both groups of bacteria. The docking analysis demonstrated the appropriate fitting of 2-(3-(9H-fluoren-9-ylideneaminooxy)-2-hydroxy-propylamino)-3-methyl-butanoic acid in human β₂-adrenergic receptor active site. Potential drug toxicity for some active compounds has also been predicted.