Reading the unique DNA methylation landscape of the brain: Non-CpG methylation,hydroxymethylation, and MeCP2

DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.     

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles

Background Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10⁻⁶). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma     

Influenza vaccination: incidence of symptoms and resulting absenteeism in hospital employees.

A convenience sample of hospital workers, those receiving influenza vaccine and those not receiving vaccine, were asked to complete questionnaires delineating the occurrence of symptoms (e.g., fever, headache, extreme tiredness, dry cough, sore throat, runny nose, stuffy nose, muscle aches) and absenteeism in the 7-day period post-vaccination if vaccinated. Those unvaccinated completed the questionnaire in a self-selected 7 consecutive day period during the study conducted from November 2004 to February 2005. Those receiving either Fluzone or FluMist reported significantly fewer symptoms and related absenteeism than the unvaccinated group (p < .05). Administration of influenza vaccine did not result in higher rates of post-vaccination symptoms as compared to an unvaccinated group. Further, vaccinated employees did not experience higher absenteeism rates as a result of receiving either influenza vaccine. However, for those reporting absenteeism as a result of symptoms, mean absenteeism days were highest in the FluMist group (4.5 days) compared to the unvaccinated group (2.1 days) and the Fluzone group (1.9 days).     

Greenstick intercondylar fracture of the distal humerus. A case report

A greenstick intercondylar fracture of the distal humerus occurred in a 14-year-old boy. The minimal displacement and stability of the injury allowed early range of motion with healing in an anatomic position and restoration of the preinjury arc of motion.     

Abdominal lymph flow response to intraperitoneal fluid in awake sheep

Lymphatic vessels are important in draining excess fluid from the abdominal space and preventing ascites. In sheep, diaphragmatic lymph vessels draining the abdominal space run to the caudal mediastinal lymph node and efferent vessels from the node drain into veins in the neck. To estimate the lymph flow response to excess intraperitoneal fluid in sheep, we cannulated a caudal mediastinal node efferent lymphatic in 5 sheep. After the sheep recovered from the surgery, the lymph flow (QL) was 154 +/- 161 (SD) microliters/min and the lymph protein concentration (CL) was 3.7 +/- 9 g/dl. Lymph flow decreased linearly with increases in lymphatic outflow pressure greater than 6 cmH2O. From this linear QL vs. outflow pressure relationship, we estimated the effective pressure driving lymph flow as the outflow pressure at which QL = 0. At baseline, the driving pressure was 24.7 +/- 14.0 cmH2O. After we infused Ringers solution (10% body weight) into the abdominal space, QL increased significantly to 7.0 +/- 4.1 times baseline and CL decreased significantly to 0.7 +/- 0.6 g/dl. Although the abdominal pressure increased significantly from 10.6 +/- 2.8 cmH2O to 15.8 +/- 2.1 cmH2O, we found no increase in lymphatic driving pressure.     

Treatment of pigment epithelial detachments due to age-related macular degeneration with intra-ocular C3F8 injection*

Purpose: To flatten pigment epithelial detachments (PED) cue to age-related macular degeneration in an attempt to visualize the underlying choroidal neovascularization by fluorescein angiography (FA) and reveal a treatment target. Methods: Nine patients with PED received intravitreal gas injections via the pars plana and postured face down. Fluorescein angiograms were obtained before and after gas injection. In two patients, retinal scotopic sensitivity was also measured. Results: Eight patients demonstrated change in the shape and size of the PED following gas injection. Four patients showed a better delineation of underlying structures on FA. Three patients had focal laser treatment to the newly visible choroidal neovascular complex, but this was successful in only one patient with flattening of the PED. Conclusion: Pigment epithelial detachments can be modified by intravitreal gas injection in some patients, but this treatment did not have a major impact on overall outcome or management.     

Synthesis of boron-containing heterocyclic compounds.

The synthesis of boron-containing 1,3,5-triazines and 1,2,4-triazines is described. Derivatives of 1,3,5-triazine containing the o-carborane cluster have been obtained by reacting the corresponding propargyl derivatives with B(10)H(14). Derivatives of 1,2,4-triazine containing the B(12)H(12)(2-) cluster have been obtained by nucleophilic substitution of ethylsulfone derivatives with B(12)H(11)SH(2-). They have been isolated in their ring-protonated form. Reaction of RNH(2)-B(8)H(11)NH-R with stericly demanding heterocycles failed, either for steric or for solubility reasons.