Photoredox catalysis harvesting multiple photon or electrochemical energies.

Photoredox catalysis (PRC) is a cutting-edge frontier for single electron-transfer (SET) reactions, enabling the generation of reactive intermediates for both oxidative and reductive processes via photon activation of a catalyst. Although this represents a significant step towards chemoselective and, more generally, sustainable chemistry, its efficacy is limited by the energy of visible light photons. Nowadays, excellent alternative conditions are available to overcome these limitations, harvesting two different but correlated concepts: the use of multi-photon processes such as consecutive photoinduced electron transfer (conPET) and the combination of photo- and electrochemistry in synthetic photoelectrochemistry (PEC). Herein, we review the most recent contributions to these fields in both oxidative and reductive activations of organic functional groups. New opportunities for organic chemists are captured, such as selective reactions employing super-oxidants and super-reductants to engage unactivated chemical feedstocks, and scalability up to gram scales in continuous flow. This review provides comparisons between the two techniques (multi-photon photoredox catalysis and PEC) to help the reader to fully understand their similarities, differences and potential applications and to therefore choose which method is the most appropriate for a given reaction, scale and purpose of a project.

Physicians' Acceptance of Triage Guidelines in the Context of the COVID-19 Pandemic: A Qualitative Study.

Aims: One of the major ethical challenges posed by the Covid-19 pandemic comes in the form of fair triage decisions for critically ill patients in situations where life-saving resources are limited. In Spring 2020, the Swiss Academy of Medical Sciences (SAMS) issued specific guidelines on triage for intensive-care treatment in the context of the Covid-19 pandemic. While evidence has shown that the capacities of intensive care medicine throughout Switzerland were sufficient to take care of all critically ill patients during the first wave of the outbreak, no evidence is available regarding the acceptance of these guidelines by ICU staff. The aim of this qualitative study was to explore the acceptance and perceived implementation of the SAMS guidelines among a sample of senior physicians involved in the care of Covid-19 patients in the Canton of Ticino. Specific objectives included capturing and describing physicians' attitudes toward the guidelines, any challenges experienced in their application, and any perceived factors that facilitated or would facilitate their application. Methods: We conducted face-to-face and telephone interviews with a purposive sample of nine senior physicians employed as either head of unity, deputy-head of unit, or medical director in either one of the two Covid-19 hospitals in the Canton of Ticino during the peak of the outbreak. Interviews were transcribed verbatim and thematically analyzed using an inductive approach. Results: We found that participants held different views regarding the nature of the guidelines, saw decisions on admission as a matter of collective responsibility, argued that decisions should be based on a medical futility principle rather than an age criterion, and found that difficulties to address end-of-life issues led to a comeback of paternalism. Conclusions: Results highlight the importance of clarifying the nature of the guidelines, establishing authority, and responsibility during triaging decisions, recognizing and addressing sources of interference with patients' autonomy, and the need of a cultural shift in timely and efficiently addressing end-of-life issues.

Chromobacterium violaceum bacteraemia: a new entity in Switzerland.

We report the uncommon clinical case of our patient, an 83-year-old woman with Alzheimer disease, who acquired a potentially fatal tropical infection in an open-air swimming pool in the Alps. Chromobacterium violaceum is a rare gram-negative anaerobe bacillus, generally associated with serious waterborne infections in tropical and subtropical regions. The patient presented to our emergency department with a 2-day history of fever and a small non-necrotic wound on the right leg after a minor injury 9 days before. It turned out to be the first infection in Switzerland due to C. violaceum, a deadly bacterium typical of tropical regions. C. violaceum appeared for the first time in Europe in the 2011. This is now the third documented case in less than a year and the second autochthonous infection ever in our continent. A delay in adequate treatment of this emerging pathogen may be associated with high fatality rates.

Nitric oxide mediates the blood pressure response to mental stress in humans.

OBJECTIVE: Nitric oxide (NO) regulates arterial pressure by modulating peripheral vascular tone and sympathetic vasoconstrictor outflow. NO synthesis is impaired in several major cardiovascular disease states. Loss of NO-induced vasodilator tone and restraint on sympathetic outflow could result in exaggerated pressor responses to mental stress. METHODS: We, therefore, compared the sympathetic (muscle sympathetic nerve activity) and haemodynamic responses to mental stress performed during saline infusion and systemic inhibition of NO-synthase by NG-monomethyl-L-arginine (L-NMMA) infusion. RESULTS: The major finding was that mental stress which during saline infusion increased sympathetic nerve activity by ~50 percent and mean arterial pressure by ~15 percent had no detectable sympathoexcitatory and pressor effect during L-NMMA infusion. These findings were not related to a generalised impairment of the haemodynamic and/or sympathetic responsiveness by L-NMMA, since the pressor and sympathetic nerve responses to immersion of the hand in ice water were preserved during L-NMMA infusion. CONCLUSION: Mental stress causes pressor and sympathoexcitatory effects in humans that are mediated by NO. These findings are consistent with the new concept that, in contrast to what has been generally assumed, under some circumstances, NO has a blood pressure raising action in vivo.

Interaction between nitric oxide and the cholinergic and sympathetic nervous system in cardiovascular control in humans.

Evidence has accumulated indicating that the interaction between NO and the autonomic nervous system plays an important role in cardiovascular regulation, not only in experimental animals, but also in humans. NO interacts with the autonomic nervous system both at the central level and peripherally. In this review, we will summarize the current understanding of this interaction in normal humans, and discuss pathophysiological consequences that occur, when this interaction is altered. We provide evidence for the concept that the primary effect of NO in humans is a reduction of basal sympathetic vasoconstrictor tone, rather than inhibition of the excitability of this system. Impaired NO synthesis in humans therefore promotes sustained vasoconstriction by 2 distinct mechanisms: loss of vasodilator tone at vascular smooth muscle cells and by facilitating central neural vasoconstrictor outflow. Insulin resistance, essential hypertension and end-stage renal failure are examples of diseases, where impaired NO buffering of neural outflow may contribute to sustained sympathetic activation. In addition to the sympathetic nervous system, NO also interacts with the cholinergic nervous system. Cholinergic mechanisms play a major, hitherto unrecognised, role in offsetting the arterial hypertension and cardiac sympathetic activation caused by inhibition of NO synthesis in normal humans. While further studies are needed to determine the exact underlying mechanism(s) by which NO and the autonomic nervous system interact in humans, these findings provide the conceptual framework for the use of therapeutic interventions that deliver NO and/or modulate the bioavailability of endogenously produced NO to adjust the autonomic control of the circulation in humans.

Defective respiratory amiloride-sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice.

Pulmonary oedema results from an imbalance between the forces driving fluid into the airspace and the biological mechanisms for its removal. In mice lacking the alpha-subunit of the amiloride-sensitive sodium channel (alphaENaC(-/-)), impaired sodium transport-mediated lung liquid clearance at birth results in neonatal death. Transgenic expression of alphaENaC driven by a cytomegalovirus (CMV) promoter (alphaENaC(-/-)Tg+) rescues the lethal pulmonary phenotype, but only partially restores respiratory sodium transport in vitro. To test whether this may also be true in vivo, and to assess the functional consequences of this defect on experimental pulmonary oedema, we measured respiratory transepithelial potential difference (PD) and alveolar fluid clearance (AFC), and quantified pulmonary oedema during experimental acute lung injury in these mice. Both respiratory PD and AFC were roughly 50% lower (P < 0.01) in alphaENaC(-/-)Tg+ than in control mice. This impairment was associated with a significantly larger increase of the wet/dry lung weight ratio in alphaENaC(-/-)Tg+ than in control mice, both after exposure to hyperoxia and thiourea. Moreover, the rate of resolution of thiourea-induced pulmonary oedema was more than three times slower (P < 0.001) in alphaENaC(-/-)Tg+ mice. alphaENaC(-/-)Tg+ mice represent the first model of a constitutively impaired respiratory transepithelial sodium transport, and provide direct evidence that this impairment facilitates pulmonary oedema in conscious freely moving animals. These data in mice strengthen indirect evidence provided by clinical studies, suggesting that defective respiratory transepithelial sodium transport may also facilitate pulmonary oedema in humans.

Relapsing acute respiratory failure induced by minocycline.

The antibiotic minocycline, which is used in the treatment of acne, has been associated with various pulmonary complications such as pulmonary lupus and hypersensitivity pneumonitis. We now report a particularly severe case of minocycline-related pulmonary toxicity that was characterized by a relapsing form of hypersensitivity eosinophilic pneumonia complicated by acute respiratory failure.

Salmeterol for the prevention of high-altitude pulmonary edema.

BACKGROUND: Pulmonary edema results from a persistent imbalance between forces that drive water into the air space and the physiologic mechanisms that remove it. Among the latter, the absorption of liquid driven by active alveolar transepithelial sodium transport has an important role; a defect of this mechanism may predispose patients to pulmonary edema. Beta-adrenergic agonists up-regulate the clearance of alveolar fluid and attenuate pulmonary edema in animal models. METHODS: In a double-blind, randomized, placebo-controlled study, we assessed the effects of prophylactic inhalation of the beta-adrenergic agonist salmeterol on the incidence of pulmonary edema during exposure to high altitudes (4559 m, reached in less than 22 hours) in 37 subjects who were susceptible to high-altitude pulmonary edema. We also measured the nasal transepithelial potential difference, a marker of the transepithelial sodium and water transport in the distal airways, in 33 mountaineers who were prone to high-altitude pulmonary edema and 33 mountaineers who were resistant to this condition. RESULTS: Prophylactic inhalation of salmeterol decreased the incidence of high-altitude pulmonary edema in susceptible subjects by more than 50 percent, from 74 percent with placebo to 33 percent (P=0.02). The nasal potential-difference value under low-altitude conditions was more than 30 percent lower in the subjects who were susceptible to high-altitude pulmonary edema than in those who were not susceptible (P<0.001). CONCLUSIONS: Prophylactic inhalation of a beta-adrenergic agonist reduces the risk of high-altitude pulmonary edema. Sodium-dependent absorption of liquid from the airways may be defective in patients who are susceptible to high-altitude pulmonary edema. These findings support the concept that sodium-driven clearance of alveolar fluid may have a pathogenic role in pulmonary edema in humans and therefore represent an appropriate target for therapy.