Muscle sympathetic nerve activity (MSNA) is greatly elevated in patients with obstructive sleep apnoea (OSA) during daytime wakefulness, leading to hypertension, but the underlying mechanisms are poorly understood. By recording MSNA concurrently with functional Magnetic Resonance Imaging (fMRI) of the brain we aimed to identify the central processes responsible for the sympathoexcitation. Spontaneous fluctuations in MSNA were recorded via tungsten microelectrodes inserted percutaneously into the common peroneal nerve in 17 OSA patients and 15 healthy controls lying in a 3 T MRI scanner. Blood Oxygen Level Dependent (BOLD) contrast gradient echo, echo-planar images were continuously collected in a 4 s ON, 4 s OFF (200 volumes) sampling protocol. Fluctuations in BOLD signal intensity covaried with the intensity of the concurrently recorded bursts of MSNA. In both groups there was a positive correlation between MSNA and signal intensity in the left and right insulae, dorsolateral prefrontal cortex (dlPFC), dorsal precuneus, sensorimotor cortex and posterior temporal cortex, and the right mid-cingulate cortex and hypothalamus. In OSA the left and right dlPFC, medial PFC (mPFC), dorsal precuneus, anterior cingulate cortex, retrosplenial cortex and caudate nucleus showed augmented signal changes compared with controls, while the right hippocampus/parahippocampus signal intensity decreased in controls but did not change in the OSA subjects. In addition, there were significant increases in grey matter volume in the left mid-insula, the right insula, left and right primary motor cortices, left premotor cortex, left hippocampus and within the brainstem and cerebellum, and significant decreases in the mPFC, occipital lobe, right posterior cingulate cortex, left cerebellar cortex and the left and right amygdala in OSA, but there was no overlap between these structural changes and the functional changes in OSA. These data suggest that the elevated muscle vasoconstrictor drive in OSA may result from functional changes within these brain regions, which are known to be directly or indirectly involved in the modulation of sympathetic outflow via the brainstem. That there was no overlap in the structural and functional changes suggests that asphyxic damage due to repeated episodes of nocturnal obstructive apnoea is not the main cause of the sympathoexcitation.
Malaria is the deadliest parasitic disease affecting over 200 million people worldwide. The increasing number of treatment failures due to multi-drug-resistant parasites in South-East Asia hinders the efforts for elimination. It is thus urgent to develop new antimalarials to contain these resistant parasites. Based on a previous report showing the presence of DNA methylation in Plasmodium, we generated new types of DNA methylation inhibitors against malaria parasites. The quinoline–quinazoline-based inhibitors kill parasites, including artemisinin-resistant field isolates adapted to culture, in the low nanomolar range. The compounds target all stages of the asexual cycle, including early rings, during a 6 h treatment period; they reduce DNA methylation in the parasite and show in vivo activity at 10 mg/kg. These potent inhibitors are a new starting point to develop fast-acting antimalarials that could be used in combination with artemisinins.
Studies previously performed in our laboratory have shown that sinusoidal galvanic vestibular stimulation (sGVS), a means of selectively modulating vestibular input without affecting other inputs, can cause partial entrainment of muscle sympathetic nerve activity (MSNA) at frequencies ranging from 0.2 to 2.0 Hz. Here we test the effect of sGVS on sympathetic outflow when stimulating the vestibular system at lower frequencies. MSNA was recorded via tungsten microelectrodes inserted into the left common peroneal nerve in 12 awake, seated subjects. Bipolar binaural sinusoidal GVS (±2 mA, 100 cycles) was applied to the mastoid processes at 0.08, 0.13 and 0.18 Hz. Cross-correlation analysis revealed two bursts of modulation of MSNA for each cycle of stimulation. We believe the primary peak is related to the positive phase of the sinusoid, in which the right vestibular nerve is hyperpolarised and the left vestibular nerve depolarised. Furthermore, we believe the secondary peak is related to the negative phase of the sinusoid (depolarisation of the right vestibular nerve and hyperpolarisation of the left vestibular nerve). This was never observed at higher frequencies of stimulation, presumably because at such frequencies there is insufficient time for a second peak to be expressed. The incidence of double peaks of MSNA was highest at 0.08 Hz and lowest at 0.18 Hz. These observations emphasise the role of the vestibular apparatus in the control of blood pressure, and further suggest convergence of bilateral inputs from vestibular nuclei onto the output nuclei from which MSNA originates, the rostral ventrolateral medulla (RVLM).
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