A New Pharmacological Approach Based on Remdesivir Aerosolized Administration on SARS-CoV-2 Pulmonary Inflammation: A Possible and Rational Therapeutic Application

The new zoonotic coronavirus (SARS-CoV-2) responsible for coronavirus disease (COVID-19) is a new strain of coronavirus not previously seen in humans and which appears to come from bat species. It originated in Wuhan, Hubei Province, China, and spread rapidly throughout the world, causing over 5,569,679 global cases and 351,866 deaths in almost every country in the world, including Europe, particularly Italy. In general, based on existing data published to date, 80.9% of patients infected with the virus develop mild infection; 13.8% severe pneumonia; 4.7% respiratory failure, septic shock or multi-organ failure; 3% of these cases are fatal. Critical patients have been shown to develop acute respiratory distress syndrome (ARDS) and hospitalization in intensive care units. The average age of patients admitted to hospital is 57–79 years, with one third half with an un- derlying disease. Asymptomatic infections have also been described, but their frequency is not known. SARS- CoV-2 transmission is mainly airborne from one person to another via droplets. The data available so far seem to indicate that SARS-CoV-2 is capable of producing an excessive immune reaction in the host. The virus attacks type II pneumocytes in the lower bronchi through the binding of the Spike protein (S protein) to viral receptors, of which the angiotensin 2 conversion enzyme (ACE2) receptor is the most important. ACE2 receptor is widely expressed in numerous tissues, including the oropharynx and conjunctiva, but mostly distributed in ciliated bronchial epithelial cells and type II pneumocytes in the lower bronchi. The arrival of SARS-CoV-2 in the lungs causes severe primary interstitial viral pneumonia that can lead to the “cytokine storm syndrome”, a deadly uncontrolled systemic inflammatory response triggered by the activation of interleukin 6 (IL-6), whose effect is extensive lung tissue damage and disseminated intravascular coagulation (DIC), that are life-threatening for patients with COVID-19. In the absence of a therapy of proven efficacy, current management consists of off-label or compassionate use therapies based on antivirals, antiparasitic agents in both oral and parenteral formulation, anti-inflammatory drugs, oxygen therapy and heparin support and convalescent plasma. Like most respiratory viruses can function and replicate at low temperatures (i.e. 34–35 °C) and assuming viral thermolability of SARS- CoV-2, local instillation or aerosol of antiviral (i.e. remdesivir) in humid heat vaporization (40°–41 °C) in the first phase of infection (phenotype I, before admission), both in asymptomatic but nasopharyngeal swab positive patients, together with antiseptic-antiviral oral gargles and povidone-iodine eye drops for conjunctiva (0,8–5% conjunctival congestion), would attack the virus directly through the receptors to which it binds, significantly decreasing viral replication, risk of evolution to phenotypes IV and V, reducing hospitalization and therefore death

The tectonic development and erosion of the knox subglacial sedimentary basin, East Antarctica

Sedimentary basins beneath the East Antarctic Ice Sheet (EAIS) have immense potential to inform models of the tectonic evolution of East Antarctica and its ice-sheet. However, even basic characteristics such as thickness and extent are often unknown. Using airborne geophysical data, we resolve the tectonic architecture of the Knox Subglacial Sedimentary Basin in western Wilkes Land. In addition, we apply an erosion restoration model to reconstruct the original basin geometry for which we resolve geometry typical of a transtensional pull-apart basin. The tectonic architecture strongly indicates formation as a consequence of the rifting of India from East Gondwana from ca. 160-130 Ma, and we suggest a spatial link with the western Mentelle Basin offshore Western Australia. The erosion restoration model shows that erosion is confined within the rift margins, suggesting that rift structure has strongly influenced the evolution of the Denman and Scott ice streams

The Impact of Tuberculosis among Immigrants: Epidemiology and Strategies of Control in High-Income Countries—Current Data and Literature Review

A significant reappearance of tuberculosis (TB) was observed in industrialized countries during the last two decades. This is due to the spread of HIV infection itself and to today\u27s migratory phenomenon as a consequence of wealth disparity, poverty, wars and political persecutions. This proportion is expected to increase and represents an important cause of the overall resurgence of the TB epidemic and drug‐resistant TB in Western Europe and the USA. TB is currently one of the leading causes of death worldwide and a health problem in high‐income countries. Although WHO global TB report 2015 with its “STOP TB” strategy has the goal to eliminate TB as a public health problem by 2050, TB shows no signs of disappearing despite some decline in high‐income countries. In order to intensify the fights against this deadly disease, further efforts should be aimed to improve examination/detection processes to accurately determine all kinds of TB, and how best to enhance TB control through a coordinated medical screening program of migrants for active TB. Migration in itself is not a definitive risk for TB. Stressful living condition, social isolation, poverty, political fear/persecution, and difficulties to access to health care can expose these individuals to the risk of TB infection during and after the migration process. This chapter aims to discuss and highlight all these issues

Macrophage Activation in Follicular Conjunctivitis during the COVID-19 Pandemic

Among the symptoms of SARS-CoV-2, follicular conjunctivitis has become relevant. The conjunctiva acts as an open lymph node, reacting to the viral antigen that binds the epithelial cells, forming follicles of B cells with activated T cells and NK cells on its surface, which, in turn, talk to monocyte-derived inflammatory infected macrophages. Here, the NLRP3 inflammasome is a major driver in releasing pro-inflammatory factors such as IL-6 and caspase-1, leading to follicular conjunctivitis and bulbar congestion, even as isolated signs in the ‘asymptomatic’ patient

Calsequestrin-1 is Required for Association but not for Targeting of Triadin to the Junctional Sarcoplasmic Reticulum Membranes

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2023 Update on Sepsis and Septic Shock in Adult Patients: Management in the Emergency Department

Background: Sepsis/septic shock is a life-threatening and time-dependent condition that requires timely management to reduce mortality. This review aims to update physicians with regard to the main pillars of treatment for this insidious condition. Methods: PubMed, Scopus, and EMBASE were searched from inception with special attention paid to November 2021–January 2023. Results: The management of sepsis/septic shock is challenging and involves different pathophysiological aspects, encompassing empirical antimicrobial treatment (which is promptly administered after microbial tests), fluid (crystalloids) replacement (to be established according to fluid tolerance and fluid responsiveness), and vasoactive agents (e.g., norepinephrine (NE)), which are employed to maintain mean arterial pressure above 65 mmHg and reduce the risk of fluid overload. In cases of refractory shock, vasopressin (rather than epinephrine) should be combined with NE to reach an acceptable level of pressure control. If mechanical ventilation is indicated, the tidal volume should be reduced from 10 to 6 mL/kg. Heparin is administered to prevent venous thromboembolism, and glycemic control is recommended. The efficacy of other treatments (e.g., proton-pump inhibitors, sodium bicarbonate, etc.) is largely debated, and such treatments might be used on a case-to-case basis. Conclusions: The management of sepsis/septic shock has significantly progressed in the last few years. Improving knowledge of the main therapeutic cornerstones of this challenging condition is crucial to achieve better patient outcomes

A Calcium- and GTP-Dependent Transglutaminase in Leishmania infantum

While human and animal leishmaniasis affect several millions of people worldwide, L. infantum is the species responsible for visceral leishmaniasis in Europe, Middle East, and America. Antileishmanial drugs present issues associated with drug toxicity and increasing parasite resistance. Therefore, the study of this parasite with a focus on new potential drug targets is extremely useful. Accordingly, we purified and characterized a transglutaminase (TGase) from L. infantum promastigotes. While Tgases are known to be involved in cell death and autophagy, it appears that these functions are very important for parasites' virulence. For the first time, we showed a Ca2+- and GTP-dependent TGase in Leishmania corresponding to a 54 kDa protein, which was purified by two chromatographic steps: DEAE-Sepharose and Heparin-Sepharose. Using polyclonal antibodies against a 50-amino-acid conserved region of the catalytic core of human TGase 2, we revealed two other bands of 66 and 75 kDa. The 54 kDa band appears to be different from the previously reported TGase, which was shown to be Ca2+- independent. Future research should address the identification of the purified enzyme sequence and, subsequently, its cloning to more comprehensively investigate its pathophysiological function and possible differences from mammal enzymes

Interactions of melatonin with mammalian mitochondria. Reducer of energy capacity and amplifier of permeability transition.

Melatonin, a metabolic product of the amino acid tryptophan, induces a dose-dependent energy drop correlated with a decrease in the oxidative phosphorylation process in isolated rat liver mitochondria. This effect involves a gradual decrease in the respiratory control index and significant alterations in the state 4/state 3 transition of membrane potential (ΔΨ). Melatonin, alone, does not affect the insulating properties of the inner membrane but, in the presence of supraphysiological Ca2+, induces a ΔΨ drop and colloid-osmotic mitochondrial swelling. These events are sensitive to cyclosporin A and the inhibitors of Ca2+ transport, indicative of the induction or amplification of the mitochondrial permeability transition. This phenomenon is triggered by oxidative stress induced by melatonin and Ca2+, with the generation of hydrogen peroxide and the consequent oxidation of sulfydryl groups, glutathione and pyridine nucleotides. In addition, melatonin, again in the presence of Ca2+, can also induce substantial release of cytochrome C and AIF (apoptosis-inducing factor), thus revealing its potential as a pro-apoptotic agent