Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children

Background

Primary mediastinal large B-cell lymphoma is a rare lymphoma accounting for no more than 3% of all B-cell lymphomas in children and adolescents. However, patients in this young age group with this lymphoma have the shortest event-free survival of patients with any B-cell lymphoma under current standard chemotherapy protocols. Lymphomas with features intermediate between primary mediastinal large B-cell lymphoma and classical Hodgkin’s lymphoma (mediastinal gray zone lymphomas) have been acknowledged in the latest World Health Organization classification. Recent studies suggest that mediastinal gray zone lymphomas have an aggressive clinical course whereas patients, at least adult ones, with primary mediastinal large B-cell lymphoma might respond very well to chemotherapy in combination with anti-CD20 antibody.

Design and Methods

We aimed to evaluate whether biological differences or so far unrecognized admixed mediastinal gray zone lymphomas might explain the relatively poor outcome of pediatric patients with apparent primary mediastinal large B-cell lymphoma. We, therefore, performed a retrospective histopathological, immunohistochemical and interphase cytogenetic analysis of 52 pediatric lymphomas.

Results

The childhood primary mediastinal large B-cell lymphomas (n=44) showed a similar pattern of histology, immunophenotype and gains at 9p (59%) and 2p (41%) as adult cases, as determined from published data. We identified only four so far unrecognized cases of mediastinal gray zone lymphoma among 52 lymphomas registered in previous trials.

Conclusions

Mediastinal gray zone lymphoma is very rare in children and adolescents. It does, therefore, seem unlikely that these lymphomas account for the unsatisfactory clinical results with current therapy protocols in pediatric patients. These data have major implications for the design of future treatment protocols for mediastinal lymphomas in children and adolescents.     

Phytol,a diterpene alcohol,inhibits the inflammatory response by reducing cytokine production and oxidative stress

Studies have shown that diterpenes have anti‐inflammatory and redox‐protective pharmacological activities. The present study aimed to investigate the anti‐inflammatory properties of phytol, a diterpene alcohol, in a mouse model of acute inflammation, and phytol effect on leukocyte recruitment, cytokines levels, and oxidative stress. The anti‐inflammatory activities of phytol were assessed by measuring paw edema induced by different inflammatory agents (e.g., λ‐carrageenan, compound 48/80, histamine, serotonin, bradykinin, and prostaglandin E₂ [PGE₂]), myeloperoxidase (MPO) activity, peritonitis model and cytokine levels. Further, oxidative stress was evaluated by determining glutathione (GSH) levels and malondialdehyde (MDA) concentration. The results showed that phytol (7.5, 25, 50, and 75 mg/kg) significantly reduced carrageenan‐induced paw edema, in a dose‐dependent manner. In addition, phytol (75 mg/kg) inhibited compound 48/80‐, histamine‐, serotonin‐, bradykinin‐ and PGE₂‐induced paw edema. It also inhibited the recruitment of total leukocytes and neutrophils; decreased MPO activity, tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) levels, and MDA concentration; and increased GSH levels during carrageenan‐induced acute inflammation. These results suggest that phytol attenuates the inflammatory response by inhibiting neutrophil migration that is partly caused by reduction in IL‐1β and TNF‐α levels and oxidative stress.     

A novel RT-PCR for the detection of Helicobacter pylori and identification of clarithromycin resistance mediated by mutations in the 23S rRNA gene

In this study we evaluated the commercially available LightMix® RT-PCR assay for Helicobacter pylori detection and identification of clarithromycin (CLR) resistance in culture and clinical specimens (gastric biopsies and stool). The H. pylori LightMix® RT-PCR detects a 97 bp long fragment of the 23S rRNA gene and allows the identification of 3 distinct point mutations conferring CLR resistance via melting curve analysis. The performance of the H. pylori LightMix® RT-PCR was evaluated using a set of 60 H. pylori strains showing phenotypical CLR susceptibility or CLR resistance (Minimum inhibitory concentrations from 0.016 to 256 mg/L). We found high concordance (95%) between phenotypical CLR resistance screening by E-Test® and the Lightmix® RT-PCR. Discrepant results were verified by sequencing of the 23S rRNA gene that always confirmed the results obtained by Lightmix® RT-PCR. Furthermore, H. pylori was detected in clinical biopsy and stool specimens by Lightmix® RT-PCR that identified the correct H. pylori genotype. The LightMix® RT-PCR is an accurate, sensitive and easy to use test for H. pylori and CLR resistance detection and can therefore be readily implemented in any diagnostic laboratory.     

Abrupt termination of the 2019/20 influenza season following preventive measures against COVID-19 in Denmark,Norway and Sweden

BackgroundIn mid-March 2020, a range of public health and social measures (PHSM) against the then new coronavirus disease (COVID-19) were implemented in Denmark, Norway and Sweden.AimWe analysed the development of influenza cases during the implementation of PHSM against SARS-CoV-2 in the Scandinavian countries.MethodBased on the established national laboratory surveillance of influenza, we compared the number of human influenza cases in the weeks immediately before and after the implementation of SARS-CoV-2 PHSM by country. The 2019/20 influenza season was compared with the five previous seasons.ResultsA dramatic reduction in influenza cases was seen in all three countries, with only a 3- to 6-week duration from the peak of weekly influenza cases until the percentage dropped below 1%. In contrast, in the previous nine influenza seasons, the decline from the seasonal peak to below 1% of influenza-positive samples took more than 10 weeks.ConclusionsThe PHSM against SARS-CoV-2 were followed by a dramatic reduction in influenza cases, indicating a wider public health effect of the implemented measures.     

Mutations in idiopathic cytopenia of undetermined significance assist diagnostics and correlate to dysplastic changes

Cytopenia is common in the elderly population and etiology may be difficult to assess. Here, we investigated the occurrence of mutations in patients with idiopathic cytopenia of undetermined significance and the usefulness in improving diagnostics. We included 60 patients with persistent cytopenia > 6 months without definite diagnosis of hematological neoplasm after routine assessment. Bone marrow material underwent a blinded morphology review and DNA was sequenced with a targeted 20 gene panel representing the most commonly mutated genes in myelodysplastic syndrome. Thirty seven (62%) patients carried at least one mutation at inclusion, and of these 95% carried a mutation in TET2, ASXL1, SRSF2, or DNMT3A. The most commonly mutated gene was TET2 observed in 43% of all patients. During one to eight years follow‐up seven patients progressed to a myeloid neoplasm and six of these had a detectable mutation at study entry. Median time to progression was 53 months (range 10–78), and at time of progression each patient had at least two mutations detected. Mutations in TP53 and NRAS were not present in patients at inclusion, but identified as secondary hits triggering progression. The morphology review was concordant in 68% of all cases, and 93% of the cases reclassified into the group “highly suspicious for MDS” had a mutation. All patients who had a concordant review “highly suspicious for MDS” had at least two mutations detected. Overall, we show that morphology examination is challenging in this heterogeneous group and targeted sequencing helps identify patients at risk of progression. Am. J. Hematol. 91:1234–1238, 2016. © 2016 Wiley Periodicals, Inc.     

Hydra meiosis reveals unexpected conservation of structural synaptonemal complex proteins across metazoans

The synaptonemal complex (SC) is a key structure of meiosis, mediating the stable pairing (synapsis) of homologous chromosomes during prophase I. Its remarkable tripartite structure is evolutionarily well conserved and can be found in almost all sexually reproducing organisms. However, comparison of the different SC protein components in the common meiosis model organisms Saccharomyces cerevisiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, and Mus musculus revealed no sequence homology. This discrepancy challenged the hypothesis that the SC arose only once in evolution. To pursue this matter we focused on the evolution of SYCP1 and SYCP3, the two major structural SC proteins of mammals. Remarkably, our comparative bioinformatic and expression studies revealed that SYCP1 and SYCP3 are also components of the SC in the basal metazoan Hydra. In contrast to previous assumptions, we therefore conclude that SYCP1 and SYCP3 form monophyletic groups of orthologous proteins across metazoans.Most eukaryotic organisms reproduce sexually, a process that involves the fusion of gametes of the two sexes to form a new organism. A prerequisite is that the chromosome complement becomes reduced from diploid to haploid during germ cell differentiation. This is achieved during a special type of cell division, the meiosis. The original diploid state is then reconstituted during fertilization.The reduction of the chromosome number is achieved by the succession of two rounds of chromosome segregation after a single round of DNA replication. During the first and most crucial round, homologous chromosomes need to pair and go through cross-over recombination to ensure their correct segregation into two new daughter cells. The association of sister chromatids is maintained and will not be abrogated until the onset of the second round of cell division, which resembles a mitotic one.As the essential features of meiosis, i.e., pairing and cross-over recombination of homologs, can be found in a wide range of different taxonomic groups, it is assumed that meiosis evolved only once early in eukaryotic life (1). The meiotic recombination machinery, which is responsible for the synthesis of crossing over, shows strong evolutionary conservation and can be found in the meiotic model organisms from the yeast Saccharomyces cerevisiae across Caenorhabditis elegans and Drosophila melanogaster to mammals with only little variation (2, 3). The mechanism of homology search is still not well understood, but the assembly of a proteinaceous structure known as synaptonemal complex (SC), which mediates synapsis of homologs, seems likely to be an important facilitator or stabilizer of homologous pairing (4, 5). Synaptic defects consequently impair meiosis and lead to failure of cross-over recombination and chromosome segregation (chromosome nondisjunction) in diverse organisms [for reviews see (6, 7)] that can cause aneuploidy as well as infertility (5, 8). Therefore, the functions of the SC, which is implemented by its remarkable tripartite structure, seem to be evolutionarily conserved (5).Electron microscopic data revealed that the fine structure of the SC is also well conserved in evolution. It is similar in shape to a ladder in which two parallel rodlike lateral elements (LEs) are joined by several crosswise arranged transverse filaments (TFs). Chromatin of homologous chromosomes is associated with one LE each. The central region of the SC where the TFs of opposing LEs overlap is referred to as central element (CE).In mammals, protein SYCP1 is the main constituent of TFs (9) whereas LEs are largely composed of the proteins SYCP2 and SYCP3 (10, 11). In addition to the N-terminal head domain of SYCP1 molecules, the CE is composed of the CE-specific proteins SYCE1, SYCE2, SYCE3, and Tex12 [(12–14); for review see (15)]. SYCP1 and SYCP3 are particularly interesting as they are the only bona fide structural SC proteins so far characterized in mammals (16). SYCP3 can self-assemble in the absence of other SC proteins, thereby forming thin fibrils that can associate laterally to generate higher-order structures resembling LEs (16, 17). SYCP1 forms so-called polycomplexes on its own that represent stacks of normally appearing SC central regions (17).As the fine structure of the SC is well conserved in evolution, it is reasonable to assume that this would be also the case for the structural protein components. However, according to the literature, this is apparently not the case. Comparison of LE or TF protein components in the most commonly used meiosis model organisms—S. cerevisiae, Arabidopsis thaliana, C. elegans, D. melanogaster, and Mus musculus—revealed very little sequence similarity between these proteins.The emerging picture is rather puzzling. On the one hand, the SC shows a conserved ladderlike organization from yeast to human and plays a key role in meiotic recombination. On the other hand, SC''s protein composition appears to be not conserved, which suggests that the SC might have evolved independently in different taxonomic groups (5, 6, 18). To address this apparent discrepancy we performed comparative bioinformatic and expression studies focused on SC structural proteins in the basal metazoan Hydra. We provide clear evidence that, in contrast to previous assumptions, SYCP1 and SYCP3 form monophyletic groups of orthologous SC proteins across metazoans down to organisms as basal as Hydra.     

Seroprevalence of Bordetella pertussis antibodies in mothers and their newborn infants

BACKGROUND: Pertussis is a highly communicable, vaccine-preventable respiratory disease. Although the largest number of reported cases is among young infants, the most rapidly increasing incidence in the USA is in adolescents and young adults. Importantly, adult family members are the likely major reservoir, infecting susceptible infants before completion of childhood vaccination. We studied maternal-neonatal paired blood samples for the presence of pertussis-related antibodies to assess level of immunity and passive transplacental antibody passage. METHODS. Unselected maternal-neonatal cord blood samples were collected from 101 term deliveries in a single urban uninsured/underinsured hospital setting. Sera were analyzed for anti-pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) IgG antibodies by enzyme-linked immunosorbent assay (ELISA). Antibody titers were calculated using reference line methodology. Antibody values were log-transformed to establish geometric mean titers (GMT) for analysis. Student's t-test, Mann-Whitney, Pearson correlation and chi square were used for statistical comparisons as appropriate. RESULTS. Mean (SD) maternal age, gestational age and birth weight were 26.8 (6.8) years, 38.9 (1.4) weeks and 3239 (501) g, respectively. Detectable maternal levels of anti-PT, FHA and PRN were found in 34.7%, 95.0% and 80.2%, respectively. Maternal GMT (SD) for PT, FHA and PRN were 4.4 (2.6), 26.6 (3.1) and 12.3 (2.9), respectively. There was no significant relationship between PT, FHA or PRN detection or antibody GMT and maternal age. Maternal anti-PT, FHA and PRN were highly correlated with neonatal cord blood values. CONCLUSION: Despite previous childhood immunization, a large number of parous women have low or undetectable pertussis-related antibody levels, suggesting susceptibility to infection. Even with efficient transplacental passage of these antibodies, neonates similarly have limited measurable protection as detected by cord blood sampling. These data support the need for adolescent or adult vaccination against Bordetella pertussis. Healthcare providers and their clients should be aware of the risk for infant infection via family member transmission.     

Prevalence of rotavirus and human bocavirus in immunosuppressed individuals after renal transplantation in the Northern Region of Brazil

Immunosuppressive therapy causes severe impairment of host defense and diarrhea is a frequent complication in renal transplant recipients. This study aimed to describe the occurrence of Rotavirus A (RVA) and Human Bocavirus (HBoV) in fecal samples of immunosuppressed patients submitted to renal transplantation during posttransplant follow-up. A longitudinal study was carried out involving a 25-patient cohort, selected for kidney transplantation. A total of 126 fecal samples were collected between May 2014 and May 2016. Molecular techniques were used to detect and characterize circulating RVA and HBoV genotypes and statistical analysis were applied to verify the association between epidemiological and clinical characteristics. The prevalence of RVA and HBoV was 24% (6/25) and 40% (10/25), respectively. Among RVA and HBoV positive cases, the majority was female; did not conduct water treatment nor had adequate sewage facilities. The most detected genotypes were RVA G3 (62.5%) and HBoV-3 (95%). Phylogenetic analysis of HBoV strains indicated that studied samples were similar to those found in Asian and American countries. The present study point out the circulation of these viral agents among immunosuppressed individuals and these findings will enable the construction of new knowledge and care perspectives on the cause of diarrhea in this population.