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Cytosine methylation is a conserved epigenetic feature found throughout the phylum Platyhelminthes
(2013)
Background: The phylum Platyhelminthes (flatworms) contains an important group of bilaterian organisms responsible for many debilitating and chronic infectious diseases of human and animal populations inhabiting the planet today. In addition to their biomedical and veterinary relevance, some platyhelminths are also frequently used models for understanding tissue regeneration and stem cell biology. Therefore, the molecular (genetic and epigenetic) characteristics that underlie trophic specialism, pathogenicity or developmental maturation are likely to be pivotal in our continued studies of this important metazoan group. Indeed, in contrast to earlier studies that failed to detect evidence of cytosine or adenine methylation in parasitic flatworm taxa, our laboratory has recently defined a critical role for cytosine methylation in Schistosoma mansoni oviposition, egg maturation and ovarian development. Thus, in order to identify whether this epigenetic modification features in other platyhelminth species or is a novelty of S. mansoni, we conducted a study simultaneously surveying for DNA methylation machinery components and DNA methylation marks throughout the phylum using both parasitic and non-parasitic representatives.
Results: Firstly, using both S. mansoni DNA methyltransferase 2 (SmDNMT2) and methyl-CpG binding domain protein (SmMBD) as query sequences, we illustrate that essential DNA methylation machinery components are well conserved throughout the phylum. Secondly, using both molecular (methylation specific amplification polymorphism, MSAP) and immunological (enzyme-linked immunoabsorbent assay, ELISA) methodologies, we demonstrate that representative species (Echinococcus multilocularis, Protopolystoma xenopodis, Schistosoma haematobium, Schistosoma japonicum, Fasciola hepatica and Polycelis nigra) within all four platyhelminth classes (Cestoda, Monogenea, Trematoda and 'Turbellaria') contain methylated cytosines within their genome compartments.
Conclusions: Collectively, these findings provide the first direct evidence for a functionally conserved and enzymatically active DNA methylation system throughout the Platyhelminthes. Defining how this epigenetic feature shapes phenotypic diversity and development within the phylum represents an exciting new area of metazoan biology.
Background: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity.
Objective: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus.
Methods: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%).
Results: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of <= 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades <= 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions >= 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome.
(1) Background: Evaluation of impact of adjuvant radiation therapy (RT) in patients with oral squamous cell carcinoma of the oral cavity/oropharynx (OSCC) of up to 4 cm (pT1/pT2) and solitary ipsilateral lymph node metastasis (pN1). A non-irradiated group with clinical follow-up was chosen for control, and survival and quality of life (QL) were compared; (2) Methods: This prospective multicentric comprehensive cohort study included patients with resected OSCC (pT1/pT2, pN1, and cM0) who were allocated into adjuvant radiation therapy (RT) or observation. The primary endpoint was overall survival. Secondary endpoints were progression-free survival and QL after surgery; (3) Results: Out of 27 centers, 209 patients were enrolled with a median follow-up of 3.4 years. An amount of 137 patients were in the observation arm, and 72 received adjuvant irradiation. Overall survival did not differ between groups (hazard ratio (HR) 0.98 [0.55–1.73], p = 0.94). There were fewer neck metastases (HR 0.34 [0.15–0.77]; p = 0.01), as well as fewer local recurrences (HR 0.41 [0.19–0.89]; p = 0.02) under adjuvant RT. For QL, irradiated patients showed higher values for the symptom scale pain after 0.5, two, and three years (all p < 0.05). After six months and three years, irradiated patients reported higher symptom burdens (impaired swallowing, speech, as well as teeth-related problems (all p < 0.05)). Patients in the RT group had significantly more problems with mouth opening after six months, one, and two years (p < 0.05); (4) Conclusions: Adjuvant RT in patients with early SCC of the oral cavity and oropharynx does not seem to influence overall survival, but it positively affects progression-free survival. However, irradiated patients report a significantly decreased QL up to three years after therapy compared to the observation group.
Background
Telemedicine improves the quality of acute stroke care in rural regions with limited access to specialized stroke care. We report the first 2 years' experience of implementing a comprehensive telemedical stroke network comprising all levels of stroke care in a defined region.
Methods
The TRANSIT-Stroke network covers a mainly rural region in north-western Bavaria (Germany). All hospitals providing acute stroke care in this region participate in TRANSIT-Stroke, including four hospitals with a supra-regional certified stroke unit (SU) care (level III), three of those providing teleconsultation to two hospitals with a regional certified SU (level II) and five hospitals without specialized SU care (level I). For a two-year-period (01/2015 to 12/2016), data of eight of these hospitals were available; 13 evidence-based quality indicators (QIs) related to processes during hospitalisation were evaluated quarterly and compared according to predefined target values between level-I- and level-II/III-hospitals.
Results
Overall, 7881 patients were included (mean age 74.6 years +/- 12.8; 48.4% female). In level-II/III-hospitals adherence of all QIs to predefined targets was high ab initio. In level-I-hospitals, three patterns of QI-development were observed: a) high adherence ab initio (31%), mainly in secondary stroke prevention; b) improvement over time (44%), predominantly related to stroke specific diagnosis and in-hospital organization; c) no clear time trends (25%). Overall, 10 out of 13 QIs reached predefined target values of quality of care at the end of the observation period.
Conclusion
The implementation of the comprehensive TRANSIT-Stroke network resulted in an improvement of quality of care in level-I-hospitals.
Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (PAgP-Ger < 0.05; PCAD < 5 × 10−8; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95% CI = [1.02–1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95% CI = [1.05–1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense.