Postural tachycardia syndrome (PoTS) is a poorly understood but important cause of orthostatic intolerance resulting from cardiovascular autonomic dysfunction. PoTS is distinct from the syndromes of autonomic failure usually associated with orthostatic hypotension, such as pure autonomic failure and multiple system atrophy. Individuals affected by PoTS are mainly young (aged between 15 years and 40 years) and predominantly female. The symptoms--palpitations, dizziness and occasionally syncope--mainly occur when the patient is standing upright, and are often relieved by sitting or lying flat. Common stimuli in daily life, such as modest exertion, food ingestion and heat, are now recognized to be capable of exacerbating the symptoms. Onset of the syndrome can be linked to infection, trauma, surgery or stress. PoTS can be associated with various other disorders; in particular, joint hypermobility syndrome (also known as Ehlers-Danlos syndrome hypermobility type, formerly termed Ehlers-Danlos syndrome type III). This Review describes the characteristics and neuroepidemiology of PoTS, and outlines possible pathophysiological mechanisms of this syndrome, as well as current and investigational treatments.

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The central and autonomic nervous systems can be defined by their anatomical, functional and neurochemical characteristics, but neither functions in isolation. For example, fundamental components of autonomically mediated homeostatic processes are afferent interoceptive signals reporting the internal state of the body and efferent signals acting on interoceptive feedback assimilated by the brain. Recent predictive coding (interoceptive inference) models formulate interoception in terms of embodied predictive processes that support emotion and selfhood. We propose interoception may serve as a way to investigate holistic nervous system function and dysfunction in disorders of brain, body and behaviour. We appeal to predictive coding and (active) interoceptive inference, to describe the homeostatic functions of the central and autonomic nervous systems. We do so by (i) reviewing the active inference formulation of interoceptive and autonomic function, (ii) survey clinical applications of this formulation and (iii) describe how it offers an integrative approach to human physiology; particularly, interactions between the central and peripheral nervous systems in health and disease.

Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 μg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.

Aberrant production of amyloid-b peptides by processing of the b-amyloid precursor protein leads to the formation of characteristic extracellular protein deposits which are thought to be the cause of Alzheimer's disease. Therefore, inhibiting the key enzymes responsible for amyloid-b peptide generation, b-and c-secretase may offer an opportunity to intervene with the progression of the disease. In human brain and cell culture systems a heterogeneous population of amyloid-b peptides with various truncations is detected and at present, it is unclear how they are produced. We have used a combination of surface enhanced laser desorption/ionization timeof-flight mass spectrometry (SELDI-TOF MS) and a specific inhibitor of c-secretase to investigate whether the production of all amyloid-b peptide species requires the action of c-secretase. Using this approach, we demonstrate that the production of all truncated amyloid-b peptides except those released by the action of the nonamyloidogenic a-secretase enzyme or potentially beta-site bAPP cleaving enzyme 2 depends on c-secretase activity. This indicates that none of these peptides are generated by a separate enzyme entity and a specific inhibitor of the c-secretase enzyme should have the potential to block the generation of all amyloidogenic peptides. Furthermore in the presence of c-secretase inhibitors, the observation of increased cleavage of the membrane-bound bAPP C-terminal fragment C99 by a-secretase suggests that during its trafficking C99 encounters compartments in which a-secretase activity resides. Keywords: Alzheimer's disease, bAPP processing, c-secretase inhibitor, surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Amyloid-b (Ab) peptide is the major proteinaceous constituent of extracellular protein deposits which are characteristic of Alzheimer's disease (AD). These deposits occur either as senile plaques in the brain parenchyma or as vascular amyloid around the brain blood vessels (Glenner and Wong 1984;Masters et al. 1985). Ab peptides themselves are generated by processing of the b-amyloid precursor protein (bAPP) (Kang et al. 1987) which requires consecutive cleavages involving b-and c-secretase enzymes (Haass et al. 1992). An alternative processing pathway leads to the release of the bAPP ectodomain as secretory bAPP by cleavage within the Ab domain thereby excluding Ab peptide formation (Weidemann et al. 1989). Members of the disintegrin and metalloprotease family (ADAM) such as ADAM10 and TACE appear to mediate this alternative cleavage termed a-secretase cleavage Lammich et al. 1999). The recently cloned b-secretase enzyme BACE1 (Asp-2) (Hussain et al. 1999;Sinha et al. 1999;Vassar et al. 1999;Yan et al. 1999;Lin et al. 2000) has been shown to generate the membrane bound bAPP C-terminal fragment (C99) intermediate, which is a prerequisite for the release of Ab peptide by c-secretase as the final processing step. BACE1 is the major b-secretase responsible for the generation of Ab peptides by neurones (Cai et al....

Social isolation is likely to be recommended for older adults due to COVID-19, with ongoing reduced clinical contact suggested for this population. This has increased the need for remote memory clinics, we therefore review the literature, current practices and guidelines on organizing such remote memory clinics, focusing on assessment of cognition, function and other relevant measurements, proposing a novel pathway based on three levels of complexity: simple telephone or video-based interviews and testing using available tests (Level 1), digitized and validated methods based on standard pen-and-paper tests and scales (Level 2), and finally fully digitized cognitive batteries and remote measurement technologies (RMTs, Level 3). Pros and cons of these strategies are discussed. Remotely collected data negates the need for frail patients or carers to commute to clinic and offers valuable insights into progression over time, as well as treatment responses to therapeutic interventions, providing a more realistic and contextualized environment for data-collection. Notwithstanding several challenges related to internet access, computer skills, limited evidence base and regulatory and data protection issues, digital biomarkers collected remotely have significant potential for diagnosis and symptom management in older adults and we propose a framework and pathway for how technologies can be implemented to support remote memory clinics. These platforms are also well-placed for administration of digital cognitive training and other interventions. The individual, societal and public/private costs of COVID-19 are high and will continue to rise for some time but the challenges the pandemic has placed on memory services also provides an opportunity to embrace novel approaches. Remote memory clinics' financial, logistical, clinical and practical benefits have been highlighted by COVID-19, supporting their use to not only be maintained when social distancing legislation is lifted but to be devoted extra resources and attention to fully potentiate this valuable arm of clinical assessment and care.

1-(5-[[(2R,3S)-2-([(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholin-4-yl]methyl]-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine hydrochloride 3 is a high affinity, orally active, h-NK(1) receptor antagonist with a long central duration of action and a solubility in water of >100 mg/mL. The construction of the 5-dimethylaminomethyl 1,2,3-triazol-4-yl unit, which incorporates the solubilizing group of 3, was accomplished by thermal rearrangement of a propargylic azide in the presence of dimethylamine. Compound 3 is highly effective in pre-clinical tests that are relevant to clinical efficacy in emesis and depression.

A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA(A)alpha2 and -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.