Trinucleotide repeat disorders comprise ~20 severe, inherited, human neuromuscular and neurodegenerative disorders, which result from an abnormal expansion of repetitive sequences in the DNA. The most common of these, Huntington’s disease (HD), results from expansion of the CAG repeat region in exon 1 of the HTT gene via an unknown mechanism. Since non-coding RNAs have been implicated in the initiation and progression of many diseases, herein we focused on a circular RNA (circRNA) molecule arising from non-canonical splicing (backsplicing) of HTT pre-mRNA. The most abundant circRNA from HTT, circHTT(2-6), was found to be more highly expressed in the frontal cortex of HD patients, compared with healthy controls, and positively correlated with CAG repeat tract length. Furthermore, the mouse orthologue (mmu_circHTT(2-6)) was found to be enriched within the brain and specifically the striatum, a region enriched for medium spiny neurons that are preferentially lost in HD. Transgenic overexpression of circHTT(2-6) in two human cell lines—SH-SY5Y and HEK293—reduced cell proliferation and nuclear size without affecting cell cycle progression or cellular size, or altering the CAG repeat region length within HTT. CircHTT(2-6) overexpression did not alter total HTT protein levels, but reduced its nuclear localisation. As these phenotypic and genotypic changes resemble those observed in HD patients, our results suggest that circHTT(2-6) may play a functional role in the pathophysiology of this disease.

Background Peanut allergy affects 1%–3% of children in Western countries. Boiling peanuts has been demonstrated to result in a hypoallergenic product that may provide a safer way of inducing desensitization in peanut‐allergic patients by first inducing tolerance to boiled peanut. We aimed to assess the efficacy and safety of oral immunotherapy (OIT) using sequential doses of boiled peanuts followed by roasted peanuts for treating peanut allergy in children. Methods In this open‐label, phase 2, single‐arm clinical trial, children aged 6–18 years with a positive history of peanut allergy and positive peanut skin prick test ≥ 8 mm and/or peanut‐specific IgE ≥ 15 kU/L at screening underwent OIT involving sequential up‐dosing with 12‐hour boiled peanut for 12 weeks, 2‐hour boiled peanut for 20 weeks and roasted peanut for 20 weeks, to a target maintenance dose of 12 roasted peanuts daily. Primary outcome: proportion of children passing open‐label oral food challenge involving cumulative administration of 12 roasted peanuts (12 g peanuts; approximately 3000 mg peanut protein) 6–8 weeks after reaching the target maintenance dose. Secondary outcomes included treatment‐related adverse events and use of medications for treating allergy symptoms. Results Between 1 July 2017 and 22 June 2018, 70 participants were enrolled and commenced OIT. Desensitization was successfully induced in 56 of 70 (80%) participants. Withdrawal due to treatment‐related adverse events was infrequent (n = 3). Treatment‐related adverse events were reported in 43 (61%) participants, corresponding to a rate of 6.58 per 1000 OIT doses. Medication use associated with treatment‐related adverse events was infrequent, with rescue epinephrine use reported by three (4%) participants (0.05 per 1000 doses). Conclusion Oral immunotherapy using boiled followed by roasted peanuts represents a pragmatic approach that appears effective in inducing desensitization and is associated with a favourable safety profile.

Vascular dysfunction is an early feature of diabetic vascular disease, due to increased oxidative stress and reduced nitric oxide (NO) bioavailability. This can lead to endothelial cell senescence and clinical complications such as stroke. Cells can become senescent by shortened telomeres and oxidative stress is known to accelerate telomere attrition. Sirtuin 1 (SIRT1) has been linked to vascular health by upregulating endothelial nitric oxide synthase (eNOS), suppressing oxidative stress, and attenuating telomere shortening. Accelerated leukocyte telomere attrition appears to be a feature of clinical type 2 diabetes (T2D) and therefore the telomere system may be a potential therapeutic target in preventing vascular complications of T2D. However the effect of T2D on vascular telomere length is currently unknown. We hypothesized that T2D gives rise to shortened leukocyte and vascular telomeres alongside reduced vascular SIRT1 expression and increased oxidative stress. Accelerated telomere attrition was observed in circulating leukocytes, but not arteries, in T2D compared to control rats. T2D rats had blunted arterial SIRT1 and eNOS protein expression levels which were associated with reduced antioxidant defense capacity. Our findings suggest that hyperglycemia and a deficit in vascular SIRT1 per se are not sufficient to prematurely shorten vascular telomeres.

Background Previous research has shown diminished nasal immune function following nasal saline irrigation (NSI), returning to baseline at 6 hours. The aim of this study was to examine the immune nasal proteome before and after 14 days of nasal irrigation. Methods Seventeen healthy volunteers received either isotonic (IsoSal) or low salt (LowNa) NSI. Nasal secretions were collected before and 30 min after NSI at baseline and again after 14 days. Specimens were analyzed using mass spectrometry to detect proteins of relevance to nasal immune function. Results One thousand eight hundred and sixty-five proteins were identified with significant changes in 71 proteins, of which 23 were identified as part of the innate immune system. Baseline analysis demonstrated an increase of 9 innate proteins after NSI, most after IsoSal. After 14 days, a greater increase in innate peptides was present, with most now in the LowNa group. When NSI solutions were compared, a significant increase in 4 innate proteins, including a 211% in lysozyme, was detected in the LowNa group. Conclusion LowNa NSI demonstrates evidence of improving the innate immune secretions, especially lysozyme, in healthy volunteers.