Impact of donor-specific antibodies on long-term graft survival with pediatric liver transplantation

BACKGROUNDIn a previous paper, we reported a high prevalence of donor-specific antibody (DSA) in pediatric patients with chronic rejection and expressed the need for confirmation of these findings in a larger cohort.AIMTo clarify the importance of DSAs on long-term graft survival in a larger cohort of pediatric patients.METHODSWe performed a retrospective analysis of 123 pediatric liver transplantation (LT) recipients who participated in yearly follow-ups including Luminex testing for DSA at our center. The cohort was split into two groups according to the DSA status (DSA-positive n = 54, DSA-negative n = 69). Groups were compared with regard to liver function, biopsy findings, graft survival, need for re-LT and immunosuppressive medication.RESULTSDSA-positive pediatric patients showed a higher prevalence of chronic rejection (P = 0.01), fibrosis (P < 0.001) and re-transplantation (P = 0.018) than DSA-negative patients. Class II DSAs particularly influenced graft survival. Alleles DQ2, DQ7, DQ8 and DQ9 might serve as indicators for the risk of chronic rejection and/or allograft fibrosis. Mean fluorescence intensity levels and DSA number did not impact graft survival. Previous episodes of chronic rejection might lead to DSA development.CONCLUSIONDSA prevalence significantly affected long-term liver allograft performance and liver allograft survival in our cohort of pediatric LT. Screening for class II DSAs in combination with assessment of protocol liver biopsies for chronic antibody-mediated rejection improved early identification of patients at risk of graft loss.     

Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization

Many current experimental results show the necessity of new conceptual approaches to understand hematopoietic stem cell organization. Recently, we proposed a novel theoretical concept and a corresponding quantitative model based on microenvironment-dependent stem cell plasticity. The objective of our present work is to subject this model to an experimental test for the situation of chimeric hematopoiesis. Investigating clonal competition processes in DBA/2-C57BL/6 mouse chimeras, we observed biphasic chimerism development with initially increasing but long-term declining DBA/2 contribution. These experimental results were used to select the parameters of the mathematical model. To validate the model beyond this specific situation, we fixed the obtained parameter configuration to simulate further experimental settings comprising variations of transplanted DBA/2-C57BL/6 proportions, secondary transplantations, and perturbation of stabilized chimeras by cytokine and cytotoxic treatment. We show that the proposed model is able to consistently describe the situation of chimeric hematopoiesis. Our results strongly support the view that the relative growth advantage of strain-specific stem cells is not a fixed cellular property but is sensitively dependent on the actual state of the entire system. We conclude that hematopoietic stem cell organization should be understood as a flexible, self-organized rather than a fixed, preprogrammed process.     

Equity of access to mental health care for anxiety and depression among different ethnic groups in four large cities in the Netherlands

Social Psychiatry and Psychiatric Epidemiology - This study explored (in)equities between ethnic groups in the Netherlands regarding their access to health care for symptoms of common mental...     

Anti-N-methyl-d-aspartate receptor encephalitis in a pre-teenage girl: a case report

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is an auto-immune and paraneoplastic encephalitis which generally affects young adults. It is a multistage illness, with prominent extrapyramidal, neuropsychiatric and autonomic symptoms. The syndrome is frequently associated with an ovarian teratoma. Recently, it has become evident that anti-NMDAR encephalitis is more common in children and adolescents than was previously believed. Prognostic factors that determine a good outcome are presence of a tumour, prompt treatment and no need for admission to an intensive care unit. Increased awareness among paediatricians of this potentially life-threatening disease is important because early recognition and treatment will improve the patients’ chances of a good clinical outcome. In this case report, we describe a 9-year-old girl with behavioural changes and severe extrapyramidal symptoms due to anti-NMDAR encephalitis associated with an ovarian teratoma. She was treated with a variety of immunomodulating therapies and made a slow, but good recovery.     

The effect of nightshift on emergency registrars' clinical skills

Objective: The effect of nightshift on ED staff performance is of clinical and risk‐management significance. Previous studies have demonstrated deterioration in psychomotor skills but the present study specifically assessed the impact of nightshift on clinical performance. Methods: The ED registrars in a tertiary hospital were enrolled in a prospective observational study and served as their own controls. During nightshift, subjects were presented simulated scenarios and tested with eight clinical questions developed to Fellowship examination standard. Matched scenarios and questions for the same subjects during dayshift served as controls. Two investigators, blinded to subject identity and the setting in which questions were attempted, independently collated answers. Results: Of 22 eligible subjects, all were recruited; four were excluded owing to incomplete data. A correlation of 0.99 was observed between the independent scoring investigators. Of a possible score of 17, the median result for nightshift was 9.5 (interquartile range: 8–11); corresponding value for dayshift was 12 (interquartile range: 10–13); P= 0.047. Conclusion: Nightshift effect on clinical performance is anecdotally well known. The present study quantifies such effects, specifically for the ED setting, and paves the way for focused research. The implications for clinical governance strategies are significant, as the fraternity embraces the mandate to maintain quality emergency care 24 h per day.     

Immunophenotypic features of MELF pattern invasion in endometrial adenocarcinoma: evidence for epithelial–mesenchymal transition

Aims:  Endometrial endometrioid adenocarcinomas (EEC) may show a distinctive morphological alteration characterized by the presence of microcystic, elongated and fragmented ('MELF') glands. These changes share features of epithelial–mesenchymal transition (EMT) in carcinomas arising at other sites. The aim was to compare the immunophenotypic profile of MELF-type epithelium with conventional glandular areas of EEC.
Methods and results:  Twenty-one EEC were stained immunohistochemically for cytokeratin (CK) AE1/AE3, CK7, vimentin, oestrogen receptor, progesterone receptor and E-cadherin. Conventional tumour glands usually showed preserved membranous E-cadherin immunoreactivity with peripheral accentuation of vimentin and hormone receptor expression. MELF-type invasion was characterized by strong CK7 expression, sometimes in contrast to adjacent unstained tumour glands. MELF areas were usually negative for hormone receptors and showed reduced E-cadherin expression.
Conclusions:  The expression of hormone receptors and intermediate filaments shows specific distribution patterns within EEC. MELF pattern invasion shows an altered immunophenotype compared with conventional glandular tumour areas. These findings suggest that MELF-type invasion represents a specific tumour alteration, and the reduction in hormone receptor and E-cadherin expression would be consistent with EMT. Immunohistochemical studies of EEC should consider micro anatomical variations in immunoreactivity, since these may be relevant to tumour invasion and progression.     

Characterization of the anti-HIV effects of native lactoferrin and other milk proteins and protein-derived peptides

In a search for natural proteins with anti-HIV activity, we screened a large set of purified proteins from bovine milk and peptide fragments thereof. Because several charged proteins and peptides are known to inhibit the process of virus entry, we selected proteins with an unusual charge composition or hydrophobicity profile. In contrast with some chemically modified (strongly negative) milk proteins, unmodified alpha(s2)-, beta- and kappa-casein, as well as several negatively and positively charged fragments thereof, did not show significant inhibition of virus replication. In fact, HIV-1 replication was elevated in the presence of beta-casein or amphiphilic fragments thereof. Bovine lactoferrin (bLF), a milk protein of 80 kDa, showed considerable inhibitory activity against HIV-1 with an IC50 of 0.4 microM. Modest inhibition was obtained with lactoferricin, a highly positively charged loop domain of bLF, indicating that other domains within the native bLF protein may also be required for inhibition. bLF blocked HIV-1 variants that use either the CXCR4 or the CCR5 coreceptor. In order to obtain further insight into the mechanism of action of this antiviral protein, we selected a bLF-resistant HIV-1 variant. The bLF-resistance phenotype is mediated by the viral envelope protein, which contains two interesting mutations that have previously been associated with an altered virus-host interaction and a modified receptor-coreceptor interaction. These results demonstrate that bLF targets the HIV-1 entry process.