Invasive aspergillosis a complication severe respiratory viral infections (influenza and COVID-19)

Invasive aspergillosis is a life-threatening complication in patients with severe influenza and COVID-19 in intensive care units. Risk factors for the invasive aspergillosis development are transitory immunosuppression associated with severe influenza and COVID-19, as well as the use of glucocorticosteroids and immunosuppressive therapy. In the presence of risk factors, suspected clinical and radiological signs of invasive aspergillosis, bronchoscopy and examination of material from the lower respiratory tract are necessary: test for galactomannan, microscopy with white calcofluor staining and inoculation on Sabouraud agar medium. Voriconazole or are recommended as first-line treatment for invasive aspergillosis in patients with severe influenza and COVID-19. Amphotericin B Liposomal, Amphotericin B Lipid Complex, and Caspofungin are the alternative options for the invasive aspergillosis treatment. Combination therapy is possible. It is necessary to control the underlying disease with eliminate or reduce the severity of risk factors.

LIPID COMPLEX FROM THE BROWN SEAWEED SARGASSUM PALLIDUM (TURNER) C. AGARDH AS A HYPOLIPIDEMIC AND ANTIOXIDANT AGENT FOR A HIGH FAT DIET IN EXPERIMENT

The object of the present study was a lipid complex isolated from the thallus of the brown seaweed Sargassum pallidum (Turner) C. Agardh (Sargassum pallidum). The lipid complex of S. pallidum included glycolipids in an amount of 35.1%, neutral lipids – 26.4%, phospholipids – 8.4%, as well as photosynthetic pigments – 30.1% of the total lipids. The content of polyunsaturated fatty acids (PUFAs) was 63.5% of the total fatty acids, of which PUFAs of the n-6 family prevailed (46.5%), the amount of PUFAs of the n-3 family was 17%. Under conditions of fat load, the effect of the lipid complex of S. pallidum and the reference drug Omega-3 on the parameters of lipid metabolism and antioxidant protection in the blood plasma and liver of rats was studied. The fat load was carried out by feeding the animals for 30 days with a standard vivary diet with the addition of 2% cholesterol and 20% beef tallow of the total formulation. The addition of the S. pallidum lipid complex (1 g/kg of body weight) to the fat diet had a hypolipidemic effect, which manifested in the restoration of weight characteristics (body and specific liver’s weight), parameters of liver lipid metabolism (cholesterol, triacylglycerols, free fatty acids), esterifying function of the liver, as well as the content of lipoproteins in the blood plasma. The combined action of n-3 and n-6 PUFAs in the lipid complex of S. pallidum promoted the induction of enzymes of the glutathione circle, providing the antioxidant defense system of the organism. The lipid complex of the brown seaweed S. pallidum was not inferior to the reference preparation Omega-3 in restoration of lipid metabolism and antioxidant defense system of animals on a high-fat diet, and even surpassed that in some parameters.

Mucormycosis in burns: a review

Mucormycosis is a rare fungal infection with a high mortality rate. It presents with scattered black/necrotic ulcers, white fungal elements, and progression of wounds despite seemingly adequate debridement. Diagnosis is confirmed on wound histology, however this is often delayed. There is currently no comprehensive review of burn related mucormycosis within the literature, making this the first paper to provide evidence-based treatment guidance. We performed a review of publications from 1946 - present. There were 151 cases of mucormycosis complicating burns. The mortality rate was 54.5%, and there was a significant increase in mortality with axial body site involvement compared with isolated peripheral involvement. The standard treatment was prompt and radical debridement. Utilisation of frozen section to guide debridement aided in clinical decision making. No systemic treatment reached statistical significance, however amphotericin B trended towards significance. Although there is no strong evidence for topical amphotericin B or hyperbaric oxygen, there may be benefit in some cases. This study recommends early radical debridement in conjunction with the European Confederation of Medical Mycology guidelines of IV liposomal/lipid complex amphotericin B >5mg/kg/day, with posaconazole 800mg daily in divided doses as a salvage or oral step-down 1.

Conformational dynamics of free and membrane-bound human Hsp70 in model cytosolic and endo-lysosomal environments

The binding of the major stress-inducible human 70-kDa heat shock protein (Hsp70) to the anionic phospholipid bis-(monoacylglycero)-phosphate (BMP) in the lysosomal membrane is crucial for its impact on cellular pathology in lysosomal storage disorders. However, the conformational features of this protein-lipid complex remain unclear. Here, we apply hydrogen–deuterium exchange mass spectrometry (HDX-MS) to describe the dynamics of the full-length Hsp70 in the cytosol and its conformational changes upon translocation into lysosomes. Using wild-type and W90F mutant proteins, we also map and discriminate the interaction of Hsp70 with BMP and other lipid components of the lysosomal membrane. We identify the N-terminal of the nucleotide binding domain (residues 87–118) as the primary orchestrator of BMP interaction. We show that the conformation of this domain is significantly reorganized in the W90F mutant, explaining its inability to stabilize lysosomal membranes. Overall, our results reveal important new molecular details of the protective effect of Hsp70 in lysosomal storage diseases, which, in turn, could guide future drug development.

Cytotoxic Lactalbumin-Oleic Acid Complexes in the Human Milk Diet of Preterm Infants

Frozen storage is necessary to preserve expressed human milk for critically ill and very preterm infants. Milk pasteurization is essential for donor milk given to this special population. Due to these storage and processing conditions, subtle changes occur in milk nutrients. These changes may have clinical implications. Potentially, bioactive complexes of unknown significance could be found in human milk given to preterm infants. One such complex, a cytotoxic α-lactalbumin-oleic acid complex named “HAMLET,” (Human Alpha-Lactalbumin Made Lethal to Tumor cells) is a folding variant of alpha-lactalbumin that is bound to oleic acid. This complex, isolated from human milk casein, has specific toxicity to both carcinogenic cell lines and immature non-transformed cells. Both HAMLET and free oleic acid trigger similar apoptotic mechanisms in tissue and stimulate inflammation via the NF-κB and MAPK p38 signaling pathways. This protein-lipid complex could potentially trigger various inflammatory pathways with unknown consequences, especially in immature intestinal tissues. The very preterm population is dependent on human milk as a medicinal and broadly bioactive nutriment. Therefore, HAMLET’s possible presence and bioactive role in milk should be addressed in neonatal research. Through a pediatric lens, HAMLET’s discovery, formation and bioactive benefits will be reviewed.

Sensitive LC-MS/MS Methods for Amphotericin B Analysis in Cerebrospinal Fluid, Plasma, Plasma Ultrafiltrate, and Urine: Application to Clinical Pharmacokinetics

Neurocryptococcosis, a meningoencephalitis caused by Cryptococcus spp, is treated with amphotericin B (AmB) combined with fluconazole. The integrity of the brain-blood barrier and the composition of the cerebrospinal fluid (CSF) may change due to infectious and/or inflammatory diseases such as neurocryptococcosis allowing for the penetration of AmB into the central nervous system. The present study aimed to develop LC-MS/MS methods capable of quantifying AmB in CSF at any given time of the treatment in addition to plasma, plasma ultrafiltrate, with sensitivity compatible with the low concentrations of AmB reported in the CSF. The methods were successfully validated in the four matrices (25 μl, 5–1,000 ng ml−1 for plasma or urine; 100 μl, 0.625–250 ng ml−1 for plasma ultrafiltrate; 100 μl, 0.1–250 ng ml−1 for CSF) using protein precipitation. The methods were applied to investigate the pharmacokinetics of AmB following infusions of 100 mg every 24 h for 16 days administered as a lipid complex throughout the treatment of a neurocryptococcosis male patient. The methods allowed for a detailed description of the pharmacokinetic parameters in the assessed patient in the beginning (4th day) and end of the treatment with AmB (16th day), with total clearances of 7.21 and 4.25 L h−1, hepatic clearances of 7.15 and 4.22 L h−1, volumes of distribution of 302.94 and 206.89 L, and unbound fractions in plasma ranging from 2.26 to 3.25%. AmB was quantified in two CSF samples collected throughout the treatment with concentrations of 12.26 and 18.45 ng ml−1 on the 8th and 15th days of the treatment, respectively. The total concentration of AmB in plasma was 31 and 20 times higher than in CSF. The unbound concentration in plasma accounted for 77 and 44% of the respective concentrations in CSF. In conclusion, the present study described the most complete and sensitive method for AmB analysis in plasma, plasma ultrafiltrate, urine, and CSF applied to a clinical pharmacokinetic study following the administration of the drug as a lipid complex in one patient with neurocryptococcosis. The method can be applied to investigate the pharmacokinetics of AmB in CSF at any given time of the treatment.

Liposomal Amphotericin B Induced Acute Reactions

Three formulations of amphotericin B are available: liposomal, lipid complex and conventional. The liposomal amphotericin B is more preferred agent than other formulations because of its tolerability, safety and potent antifungal activity. However, the liposomal amphotericin B can cause infusion-related reactions. In this case report, we aimed to report a patient who developed infusion-related reactions during the treatment with the liposomal amphotericin B but eventually tolerated the prolonged infusion. In this case report, we present a patient who developed an infusion-related reaction during The liposomal amphotericin B treatment. A 26-year-old male patient with acute promyelocytic leukemia was hospitalized for the third course of chemotherapy. Due to the invasive fungal infection history in previous hospitalizations, the liposomal amphotericin B 400 mg (IV, 5 mg/kg) once daily was initiated as secondary antifungal prophylaxis. Swelling in infusion site and chest pain were reported within 10 minutes of the liposomal amphotericin B administration, and the infusion rate was slowed down to 400 mg/6 hours from 400 mg/2 hours. All these reactions disappeared with prolonged infusion time. The patient received a total of 7 liposomal amphotericin B doses subsequently without any reaction during the chemotherapy cycle. In our experience, the liposomal amphotericin B-induced infusion-related reactions can be resolved by prolonging the infusion time.