Cyclooxygenase-2 inhibitors: a new therapeutic option in the treatment of macular edema after cataract surgery

Two patients had uneventful phacoemulsification. After initial improvement, vision deteriorated because of cystoid macular edema (CME). In 1 patient, treatment with systemic nonsteroidal antiinflammatory drugs showed significant improvement in visual acuity but had to be discontinued because of side effects and a relapse of the disease. In the other patient, this therapy was not sufficient. Both patients were given valdecoxib, a cyclooxygenase-2 inhibitor. The new therapy was tolerated well and led to significant and stable improvement in visual acuity in both patients. To our knowledge, this is the first report of using a cyclooxygenase-2 inhibitor in the treatment of clinically significant CME.     

ATP-binding cassette member A3 (E292V) gene mutation and pulmonary morbidity in very-low-birth-weight infants

Aim: ATP‐binding cassette member A 3 (ABCA3) plays a critical role for the transport of surfactant phospholipids into the lamellar bodies of type II alveolar epithelial cells. Term infants carrying the E292V missense mutation of the gene encoding ABCA3 are likely to develop respiratory distress syndrome, and the mutation has also been linked to interstitial lung disease in paediatric patients. The aim of this study was to investigate the association of the E292V genotype with pulmonary morbidity in a large cohort of very‐low‐birth‐weight (VLBW) infants. Methods: We performed a genetic association study with a prospective, population‐based multi‐centre cohort of 3177 VLBW infants born in 16 German study centres between 2003 and 2009 (German Neonatal Network). The ABCA3 genotype was determined by restriction fragment length polymorphism–PCR in genomic DNA samples derived from buccal swabs. Results: In a large cohort of 3177 VLBW infants, 11 individuals were found to be heterozygote for the E292V mutation (0.34%). After stratification according to ABCA3 genotype, no differences were noted for clinical characteristics, necessary treatments and neonatal pulmonary outcomes. Conclusions: Within the size limits of our study cohort, the ABCA3 missense mutation E292V had no remarkable effect on pulmonary outcome in VLBW infants. Present results do not rule out the possibility that E292V phenotype is associated with minor difference in the morbidity.     

Impact of galactomannan testing on the prevalence of invasive aspergillosis in patients with hematological malignancies

Galactomannan (GM) is a polysaccharide component of the cell wall of Aspergillus spp. and is released into the host's circulation by growing hyphae. GM testing of patients with hematological malignancies has been rarely considered in recent epidemiologic studies of invasive mould infections (IMIs). The aim of the investigation was to analyze the impact of GM testing on the reported prevalence of IMI by comparing detection rates of IMI before and after the introduction of this diagnostic procedure. Prevalence of IMI was assessed by conducting a prospective single-centre study over seven months in 2010. Results obtained were then compared to those obtained with a representative collection of patients assessed by the same investigators at the same institution over seven months in 2007, i.e., prior to the introduction of GM testing. We found that, in general, detection rates of invasive aspergillosis (IA) and invasive mould infections increased significantly after the introduction of GM analysis. This study may therefore indicate that GM testing has a significant impact on the reported prevalence of IMI. Broad usage of such testing in patients with hematological malignancies may be able to produce a realistic picture of IMI rates when current diagnostic criteria are applied.     

Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus

The innate immune system limits viral replication via type I interferon and also induces the presentation of viral antigens to cells of the adaptive immune response. Using infection of mice with vesicular stomatitis virus, we analyzed how the innate immune system inhibits viral propagation but still allows the presentation of antigen to cells of the adaptive immune response. We found that expression of the gene encoding the inhibitory protein Usp18 in metallophilic macrophages led to lower type I interferon responsiveness, thereby allowing locally restricted replication of virus. This was essential for the induction of adaptive antiviral immune responses and, therefore, for preventing the fatal outcome of infection. In conclusion, we found that enforced viral replication in marginal zone macrophages was an immunological mechanism that ensured the production of sufficient antigen for effective activation of the adaptive immune response.     

High-Resolution Melting Analysis as a Sensitive Prescreening Diagnostic Tool to Detect KRAS , BRAF , PIK3CA , and AKT1 Mutations in Formalin-Fixed, Paraffin-Embedded Tissues

Context .-As the availability of targeted therapies for several tumor types increases, the need for rapid and sensitive mutation screening is growing. KRAS mutations constitutively activate the RAS/RAF/mitogen-activated protein kinase (MAPK) pathway and therefore play an important role in anti-epidermal growth factor receptor therapy for patients with colorectal cancers. Mutationally activated PIK3CA and AKT1 genes are promising therapeutic targets in breast cancer. In 60% to 70% of malignant melanomas, a mutation in BRAF can be found. Thus, the blocking of the oncogenic signaling induced by this mutation is now used as treatment approach. Objective .-To establish high-resolution melting assays for routinely used predictive analyses of KRAS , AKT1 , PIK3CA , and BRAF mutations. Design .-High-resolution melting assays were developed by using specifically designed primers and genomic DNA isolated either from cell lines or formalin-fixed paraffin-embedded tissues, oligonucleotides, or plasmids. Melting curve analyses were performed on the LightCyler platform and mutation analyses were additionally confirmed by Sanger sequencing. Results .-We developed high-resolution melting assays by using genomic DNA containing the desired mutation, which enabled us to detect percentages of mutated DNA (3.1% to 12.5%) mixed in a wild-type background. Assays were evaluated by hybridization probes and/or Sanger sequencing to exclude pseudogene amplification. The high-resolution melting assays were validated with genomic DNA from different tumor entities. The concordance between Sanger sequencing and high-resolution melting was 99% for KRAS exon 2 and PIK3CA exon 20 and 100% for the remaining assays. Conclusions .-High-resolution melting provides a valid and powerful tool for detecting genomic mutations efficiently.     

Age-dependent regulation of tumor-related microRNAs in the brain of the annual fish Nothobranchius furzeri

MicroRNAs are regulators of gene expression. We used miRNA-seq by the Illumina platform to quantify and compare the temporal miRNA expression profiles in the brain of a short-lived (GRZ) and a longer-lived strain (MZM) of the annual fish Nothobranchius furzeri. We used fuzzy-c-means clustering to group miRNAs with similar profiles. In MZM, we found tumor suppressors with known negative interactions with MYC and/or positive interactions with TP53 among up-regulated miRNAs (e.g. miR-23a, miR-26a/b, miR-29a/b and miR-101a) in aged animals. Conversely, we found oncogenes which are MYC targets among down-regulated miRNAs (miR-7a, members of miR cluster 17∼92). These latter were previously shown to be regulated in human replicative aging. In addition, three regulated miRNAs (miR-181c, miR-29a and miR-338) are known to be age-regulated and to globally contribute to regulation of their targets in the human brain. Therefore, there appears to be a degree of evolutionarily conservation in age-dependent miRNA expression between humans and N. furzeri. GRZ showed specific regulation of some miRNAs, notably a marked up-regulation of miR-124, a miRNA important for neuronal differentiation. The two strains differ in their miRNA expression profiles already at sexual maturity. Short lifespan in GRZ could therefore be - at least partially - due to dysregulated miRNA expression.