In-vitro and in-silico evidence for oxidative stress as drivers for RDW

Red blood cell distribution width (RDW) is a biomarker associated with a variety of clinical outcomes. While anemia and subclinical inflammation have been posed as underlying pathophysiology, it is unclear what mechanisms underlie these assocations. Hence, we aimed to unravel the mechanisms in silico using a large clinical dataset and validate our findings in vitro. We retrieved complete blood counts (CBC) from 1,403,663 measurements from the Utrecht Patient Oriented Database, to model RDW using gradient boosting regression. We performed (sex-stratified) analyses in patients with anemia, patients younger/older than 50 and validation across platforms and care settings. We then validated our hypothesis regarding oxidative stress using an in vitro approach. Only percentage microcytic (pMIC) and macrocytic (pMAC) erythrocytes and mean corpuscular volume were most important in modelling RDW (RMSE = 0.40, R 2  = 0.96). Subgroup analyses and validation confirmed our findings. In vitro induction of oxidative stress underscored our results, namely increased RDW and decreased erythrocyte volume, yet no vesiculation was observed. We found that erythrocyte size, especially pMIC, is most informative in predicting RDW, but no role for anemia or inflammation. Oxidative stress affecting the size of the erythrocytes may play a role in the association between RDW and clinical outcomes

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

Background: The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS. Methods: Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls. Results: Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients. Conclusions: In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well

Food allergy: What do we learn from animal models?

Purpose of review This review summarizes selected articles on animal models of food allergy published in 2003. The research areas that are covered include mechanistic studies, the search for new therapies, as well as screening models for hazard identification of potential allergens. Recent findings Novel treatment options of both prevention and therapeutic strategies have been reported with promising results. The induction of de-sensitization to food proteins was achieved by exposure to a mixture of recombinant food allergens and T helper 1 (Th1)-skewing bacterial components. Furthermore, research in animal models has provided new insights into the role of protein structure, digestion, and gut permeability in sensitization and tolerance induction to food proteins. The Th2 hypothesis of food allergy was tested in mouse strains, linking genetic susceptibility to sensitization with differential Th1-Th2 responses. In this context, the role of the liver in development of food antigen-specific Th2 cells, and the importance of costimulatory molecules in Th2 skewing were demonstrated. Finally, rodent models to predict potential allergenicity of novel foods have been further developed using different routes of sensitization. Summary Currently, several animal models of food allergy are used, including mouse, rat, swine, and dog. Continuing research in these models may elucidate the immunological mechanisms that underlie the sensitization and challenge phase of food allergy and may result in improved therapeutic options. Furthermore, the development of animal models to predict relative allergenicity of novel foods remains an important topic

A qualitative analysis of statements on motivation of applicants for medical school

BACKGROUND: Selection committees try to ascertain that motivated students are selected for medical school. Self-determination theory stresses that the type of motivation is more important than the quantity of motivation. Autonomous motivation, compared to controlled motivation, in students leads to better learning outcomes. Applicants can express their motivation in written statements, a selection tool which has been found to elicit heterogeneous responses, hampering the comparison of applicants. This study investigates the content of applicants’ statements on motivation for medical school in particular, the possibility to distinguish the type of motivation and the differences between selected and non-selected applicants. METHODS: A thematic analysis was conducted on written statements on motivation (n = 96), collected as a part of the selection procedure for the graduate entry program for medicine and research at our institution. Themes were identified as motivation-related and motivation-unrelated (additional). The motivation-related themes were further classified as autonomous and controlled types of motivation. Group percentages for each theme were compared between selected and non-selected applicants using Chi-square test and Fisher exact test. RESULTS: Applicants mainly described reasons belonging to autonomous type of motivation and fewer reasons belonging to controlled type of motivation. Additional themes in the statements included previous work experience and academic qualifications, ambitions, expectations and descriptions of the program and profession, personal qualities, and personal history. Applicants used strong words to support their stories. The selected and non-selected applicants did not differ in their types of motivation. Non-selected applicants provided more descriptions of personal history than selected applicants (p < 0.05). CONCLUSIONS: The statement on motivation does not appear to distinguish between applicants in selection for medical school. Both selected and non-selected applicants reported mainly autonomous motivation for applying, and included a lot of additional information, which was beyond the scope of what was asked from them. The findings raise a question mark on the validity and reliability of the statement on motivation as a tool for selection. It could however be of added value to enable applicants to tell their story, which they appreciate, and to create awareness of the program, resulting in an informed decision to apply

The mouth care item of the MOBID pain scale:secondary analyses of unique video uptakes by dental professionals

Purpose: The Mobilization-Observation-Behaviour-Intensity-Dementia (MOBID) Pain Scale has been developed for the assessment of pain in elderly individuals with severe dementia. From the initial draft of the MOBID, the teeth/mouth care item was removed due to its low correlation with the total score. However, the observation of this item was done by non-dental professionals only. The aim was to revisit the unique teeth/mouth care video uptake fragments with a group of experienced elderly care dentists, as to establish the reliability of this item. Material and methods: Using the Orofacial MOBID Pain Scale, 11 fragments were assessed by 12 specialists during two sessions with a 4-week interval. The specialists scored whether or not they observed orofacial pain/discomfort-related behaviours (pain noises, facial expressions and/or defence) and/or dementia-related behaviours (anxiety, aggression and/or confusion). The threshold for agreement in scoring was arbitrarily set at 66.6%. As a next step, reliability was quantified using Cohen's kappa. Results: For only two video fragments, substantial agreement was obtained during both sessions, while for three fragments, the agreement was substantial during one session only. In addition, only three observers were able to provide consistent scores. For two of those, the various kappa values could be qualified as moderate to good. Notably, all consistent scores pertained to dementia-related behaviours; not to orofacial pain/disability-related behaviours. Conclusion: Teeth/mouth care, as displayed on video uptakes, cannot be interpreted reliably by experienced elderly care dentists in terms of orofacial pain/discomfort-related behaviour or dementia-related behaviour with the Orofacial MOBID Pain Scal

The mouth care item of the MOBID pain scale: secondary analyses of unique video uptakes by dental professionals

Purpose: The Mobilization-Observation-Behaviour-Intensity-Dementia (MOBID) Pain Scale has been developed for the assessment of pain in elderly individuals with severe dementia. From the initial draft of the MOBID, the teeth/mouth care item was removed due to its low correlation with the total score. However, the observation of this item was done by non-dental professionals only. The aim was to revisit the unique teeth/mouth care video uptake fragments with a group of experienced elderly care dentists, as to establish the reliability of this item. Material and methods: Using the Orofacial MOBID Pain Scale, 11 fragments were assessed by 12 specialists during two sessions with a 4-week interval. The specialists scored whether or not they observed orofacial pain/discomfort-related behaviours (pain noises, facial expressions and/or defence) and/or dementia-related behaviours (anxiety, aggression and/or confusion). The threshold for agreement in scoring was arbitrarily set at 66.6%. As a next step, reliability was quantified using Cohen's kappa. Results: For only two video fragments, substantial agreement was obtained during both sessions, while for three fragments, the agreement was substantial during one session only. In addition, only three observers were able to provide consistent scores. For two of those, the various kappa values could be qualified as moderate to good. Notably, all consistent scores pertained to dementia-related behaviours; not to orofacial pain/disability-related behaviours. Conclusion: Teeth/mouth care, as displayed on video uptakes, cannot be interpreted reliably by experienced elderly care dentists in terms of orofacial pain/discomfort-related behaviour or dementia-related behaviour with the Orofacial MOBID Pain Scale. © 2014 John Wiley & Sons A/S and The Gerodontology Association

Practice variations in the management of childhood nephrotic syndrome in the Netherlands

Nephrotic syndrome in childhood is a common entity in the field of pediatric nephrology. The optimal treatment of children with nephrotic syndrome is often debated. Previously conducted studies have shown significant variability in nephrotic syndrome management, especially in the choice of steroid-sparing drugs. In the Netherlands, a practice guideline on the management of childhood nephrotic syndrome has been available since 2010. The aim of this study was to identify practice variations and opportunities to improve clinical practice of childhood nephrotic syndrome in the Netherlands. A digital structured survey among Dutch pediatricians and pediatric nephrologists was performed, including questions regarding the initial treatment, relapse treatment, kidney biopsy, additional immunosuppressive treatment, and supportive care. Among the 51 responses, uniformity was seen in the management of a first presentation and first relapse. Wide variation was found in the tapering of steroids after alternate day dosing. Most pediatricians and pediatric nephrologists (83%) would perform a kidney biopsy in case of steroid-resistant nephrotic syndrome, whereas for frequent relapsing and steroid-dependent nephrotic syndrome this was 22% and 41%, respectively. Variation was reported in the steroid-sparing treatment. Finally, significant differences were present in the supportive treatment of nephrotic syndrome.Conclusion: Substantial variation was present in the management of nephrotic syndrome in the Netherlands. Differences were identified in steroid tapering, use of steroid coverage during stress, choice of steroid-sparing agents, and biopsy practice. To promote guideline adherence and reduce practice variation, factors driving this variation should be assessed and resolved. What is Known: • National and international guidelines are available to guide the management of childhood nephrotic syndrome. • Several aspects of the management of childhood nephrotic syndrome, including the choice of steroid-sparing drugs and biopsy practice, are controversial and often debated among physicians. What is New: • Significant practice variation is present in the management of childhood nephrotic syndrome in the Netherlands, especially in the treatment of FRNS, SDNS, and SRNS. • The recommendation on the steroid treatment of a first episode of nephrotic syndrome in the KDIGO guideline leaves room for interpretation and is likely the cause of substantial differences in steroid-tapering practices among Dutch pediatricians and pediatric nephrologists