Arteriolar myogenic vasoconstriction occurs when increased stretch or membrane tension leads to smooth muscle cell depolarization and opening of voltage-gated Ca2+ channels. To prevent positive feedback and excessive pressure-induced vasoconstriction, studies in cerebral artery smooth muscle have suggested that activation of large conductance, Ca 2+ -activated K + channels (BK Ca ) provides an opposing hyperpolarizing influence reducing Ca 2+ channel activity. We have hypothesized that this mechanism may not equally apply to all vascular beds. To establish the existence of such heterogeneity in vascular reactivity, studies were performed on rat vascular smooth muscle (VSM) cells from cremaster muscle arterioles and cerebral arteries. Whole cell K + currents were determined at pipette [Ca 2+ ] of 100 nm or 5 μm in the presence and absence of the BK Ca inhibitor, iberiotoxin (IBTX; 0.1 μm). Similar outward current densities were observed for the two cell preparations at the lower pipette Ca 2+ levels. At 5 μm Ca 2+ , cremaster VSM showed a significantly (P < 0.05) lower current density compared to cerebral VSM (34.5 ± 1.9 vs 45.5 ± 1.7 pA pF −1 at +70 mV). Studies with IBTX suggested that the differences in K + conductance at 5 μm intracellular [Ca 2+ ] were largely due to activity of BK Ca . 17β-Oestradiol (1 μm), reported to potentiate BK Ca current via the channel's β-subunit, caused a greater effect on whole cell K + currents in cerebral vessel smooth muscle cells (SMCs) compared to those of cremaster muscle. In contrast, the α-subunit-selective BK Ca opener, NS-1619 (20 μm), exerted a similar effect in both preparations. Spontaneously transient outward currents (STOCs) were more apparent (frequency and amplitude) and occurred at more negative membrane potentials in cerebral compared to cremaster SMCs. Also consistent with decreased STOC activity in cremaster SMCs was an absence of detectable Ca 2+ sparks (0 of 76 cells) compared to that in cerebral SMCs (76 of 105 cells). Quantitative PCR showed decreased mRNA expression for the β1 subunit and a decrease in the β 1: α ratio in cremaster arterioles compared to cerebral vessels. Similarly, cremaster arterioles showed a decrease in total BK Ca protein and the β 1: α-subunit ratio. The data support vascular heterogeneity with respect to the activity of BK Ca in terms of both β-subunit regulation and interaction with SR-mediated Ca 2+ signalling.

Background Acute disseminated encephalomyelitis (ADEM) is a rare immune-mediated inflammatory demyelinating disease of the central nervous system. We report a case of ADEM presenting with bilateral optic neuritis temporally associated with the ChAdOx1 vaccine against SARS-COVID19 virus. Case presentation A 36-year-old female presented with bilateral optic neuritis following her first dose of the ChAdOx1 vaccine. Initial MRI Brain showed evidence of demyelination within the subcortical white matter, with no radiological involvement of the optic nerves. Visual evoked potentials were consistent with bilateral optic neuritis which was confirmed radiologically on follow up MRI. She was treated with intravenous steroids with improvement both in symptoms and radiological appearance. A pseudo-relapse occurred which was treated with a further course of intravenous steroids followed by an oral taper. The clinical, radiological and serological results were most consistent with diagnosis of ADEM. Conclusions ADEM is an exceedingly rare complication of ChAdOx1 vaccine despite millions of doses. While it is imperative clinicians remain aware of neurological complications of vaccines, the importance of vaccination to control a pandemic should not be undermined.

Auditory dysfunction under complex, dynamic listening conditions is a clinical hallmark of Alzheimer's disease (AD) but challenging to measure and manage. Here, we assessed understanding of sinewave speech (a paradigm of degraded speech perception) and general cognitive abilities in 17 AD patients, before and following a 10 mg dose of donepezil. Relative to healthy older individuals, patients had impaired sinewave speech comprehension that was selectively ameliorated by donepezil. Our findings demonstrate impaired perception of degraded speech in AD but retained perceptual learning capacity that can be harnessed by acetylcholinesterase inhibition, with implications for designing communication interventions and acoustic environments in dementia.