Journal of internal medicine
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The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. ⋯ Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit-related neuropsychiatric and neurodegenerative conditions.
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Review
RNAi therapy with givosiran significantly reduces attack rates in acute intermittent porphyria.
Acute hepatic porphyria (AHP) is a group of inherited metabolic disorders that affect hepatic heme biosynthesis. They are associated with attacks of neurovisceral manifestations that can be life threatening and constitute what is considered an acute porphyria attack. Until recently, the sole specific treatment for acute porphyria attacks consisted of the intravenous administration of hemin. ⋯ The results of clinical trials have shown that givosiran treatment leads to a rapid and sustained reduction of ALAS1 mRNA, decreased heme precursor levels, and a decreased rate of acute attacks compared with placebo. The clinical trials (phases I, II, and III) were all randomized and placebo controlled. Many patients enrolled in the initial clinical trials have continued treatment in open label extension and extended/compassionate-use programs in countries where givosiran is not yet commercially available.
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Glucagon-like peptide-1 (GLP-1) is a peptide derived from differential processing of the precursor for the hormone glucagon. It is secreted predominantly by endocrine cells in the gut epithelium in response to nutrient stimulation. Studies from the last 35 years have given us an idea about its physiological functions. ⋯ In this review, I first discuss whether the processing of proglucagon may also result in GLP-1 formation in the pancreas and in glucagon in the gut. Next, I discuss the relationship between the physiological actions of GLP-1 and the therapeutic effects of the GLP-1 receptor agonists, which are far from being congruent and generally poorly understood. These relationships illustrate both the difficulties and the benefits of bridging results obtained in the laboratory with those emerging from the clinic.
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Life expectancy is rising worldwide and increasing numbers of elderly patients are being admitted to the intensive care unit (ICU). Because ageing is associated with changes in organ function, increased frailty, reduced activities of daily living, reduced mobility, and reduced cognition, elderly patients represent a particular subgroup of ICU patients. Ethical decisions related to the appropriateness of intensive care and/or life-sustaining interventions, the withdrawing and withholding of life support, and terminal sedation are more frequent in these patients and will be discussed in this review. Such decisions must be tailored to the individual to take into consideration personal beliefs and wishes.
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Recent trends across Europe show a year-on-year increase in the number of patients with acute medical illnesses presenting to hospitals, yet there are no plans for a substantial expansion in acute hospital infrastructure or staffing to address demand. Strategies to meet increasing demand need to consider the fact that there is limited capacity in acute hospitals and focus on new care models in both hospital and community settings. ⋯ Acute hospital at home (HaH) is a care model which, thanks to advances in point of care diagnostic capability, can provide a credible model of acute medical assessment and treatment without the need for hospital transfer. Investment and training to support scaling up of HaH are key strategic aims for integrated healthcare systems.