Nasal mucoadhesive in situ gelling liquid crystalline fluid precursor system of polyene antibiotic for potential treatment of localized sinuses aspergillosis post COVID infection

Nasal mucoadhesive in situ gelling liquid crystalline precursor system (IGFPS) of nystatin was developed for localized treatment of nasal aspergillosis post COVID infection. The stimuli-sensitive sol system comprising of Monoolein (60%w/w), Oleic acid (10%w/w), Dimethyl sulfoxide (15%w/w), Poloxamer 407 (9%w/w), and the drug (2.23%w/w) exhibited a faster sol–gel transformation in situ with good swelling ability. The small angle X-ray scattering study identified the coexistence of Im3m cubic phase with hexagonal closed pack P63/mmc structures. The subzero differential scanning calorimetry studies identified entrapped interphasal water and free water in the gels with confirmation of gelation due to micellization. Mucoadhesive properties of the gel indicate these systems to prolong the residence time at the site of absorption. The gels followed Non-Newtonian flow pattern characteristic of pesudoplastic type. The oscillatory rheology revealed that high complex viscosity and lower tanδ value provided superior adhesiveness and mucoadhesion ability to the gel. The gel exhibited a drug release of 86% at the end of 8h and of Higuchi kinetics with anomalous transport. The IGFPS exhibited better in vitro antifungal activity in comparison to drug solution. The system demonstrated permeation enhancing effect undamaged cilia and no serious histological changes. Post intranasal administration the maximum concentration (11.79 ± 2.31 μg/ml) was realized in 20 min and the curve showed a decline similar to intravenous. The storage stability of the IGFPS was found to be within acceptable limits for stability. Thus, a nasal mucoadhesive in situ gelling fluid liquid crystalline precursor formulation may represent a promising novel alternative for the localized and systemic delivery of nystatin. [ FROM AUTHOR] Copyright of Journal of Dispersion Science & Technology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Transcriptome in Human Mycoses

Mycoses are infectious diseases caused by fungi, which incidence has increased in recent decades due to the increasing number of immunocompromised patients and improved diagnostic tests. As eukaryotes, fungi share many similarities with human cells, making it difficult to design drugs without side effects. Commercially available drugs act on a limited number of targets and have been reported fungal resistance to commonly used antifungal drugs. Therefore, elucidating the pathogenesis of fungal infections, the fungal strategies to overcome the hostile environment of the host, and the action of antifungal drugs is essential for developing new therapeutic approaches and diagnostic tests. Large-scale transcriptional analyses using microarrays and RNA sequencing (RNA-seq), combined with improvements in molecular biology techniques, have improved the study of fungal pathogenicity. Such techniques have provided insights into the infective process by identifying molecular strategies used by the host and pathogen during the course of human mycoses. This chapter will explore the latest discoveries regarding the transcriptome of major human fungal pathogens. Further we will highlight genes essential for host–pathogen interactions, immune response, invasion, infection, antifungal drug response, and resistance. Finally, we will discuss their importance to the discovery of new molecular targets for antifungal drugs. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2014, 2022.

Methodology, efficacy and safety of fecal microbiota transplantation in treating inflammatory bowel disease

Fecal microbiota transplantation (FMT), as an emerging therapy, can be used to treat microbiota related diseases. Progresses in donor screening, washed microbiota preparation, microbiota delivery routes, clinical administrative strategies, and long-term safety are moving FMT forward. Increasing clinical studies, especially those randomized controlled trials about ulcerative colitis and pilot real-word studies about serious inflammatory bowel disease (IBD), have been conducted. This review presents the latest findings about the efficacy, safety and methodology of FMT in treating IBD.Copyright © 2020 The Authors

Hemofilia a Adquirida E a Precariedade Da Saude Bucal: A Dificuldade Do Manejo Hematologico E Odontologico

A hemofilia A adquirida (HAa) e uma coagulopatia autoimune rara, associada a deficiencia do fator de coagulacao VIII, diagnosticada em idosos, que apresenta altas taxas de morbidade e mortalidade. Os principais sintomas sao sangramentos recorrentes, espontaneos e prolongados em regioes subcutaneas e mucosas, alem de hematomas musculares. O prolongamento isolado do Tempo de Tromboplastina Parcial Ativada (TTPA) e o Tempo de Protrombina (TP) normal, acompanhados de sangramento anormal, sugerem aprofundar a investigacao diagnostica. Por ser um disturbio autoimune, o paciente desenvolve inibidores contra o fator de coagulacao VIII, tornando o tratamento ainda mais complexo, ja que a reposicao do fator de coagulacao deficiente pode sofrer ataque dos autoanticorpos envolvidos. Medicamentos antifibrinoliticos e imunossupressores sao opcoes terapeuticas complementares. Um homem de 71 anos, branco, com historico profissional na agricultura e construcao civil, foi encaminhado a equipe de Hematologia apresentando dor nas pernas, hemartrose no joelho e hematomas extensos nos membros superiores e inferiores, relatando inicio dos sintomas apos segunda dose vacinal para Sars-Cov-2. Com historico de hipertensao arterial, artrite reumatoide e hiperplasia prostatica benigna, encontrava-se em uso de sinvastatina, enalapril, prednisona, diclofenaco sodico, carisoprodol e doxazosina. Os exames laboratoriais demonstraram hemograma, RNI, TP e plaquetograma dentro dos limites de normalidade. Ja a dosagem de fator de coagulacao VIII foi de 3% e o TTPA de 69,5 segundos, levando ao diagnostico de HAa. Por queixa de dor dentaria, o paciente foi encaminhado a Odontologia. Ao exame fisico, observou-se edentulismo superior e uso de protese total, pseudomembrana removivel a raspagem no palato, compativel clinicamente com candidose pseudomembranosa, presenca de quatro dentes inferiores com mobilidade, acumulo de biofilme bacteriano e caries. Alem disso, apresentava pequena ulceracao em labio inferior, indolor, nao endurecida a palpacao, compativel clinicamente com queilite actinica. Para as manifestacoes estomatologicas, prescreveu-se dexpantenol labial, fator de protecao solar e nistatina suspensao oral (100.000UI) para bochecho durante 7 dias, ocasionando a melhora incompleta da lesao labial e resolucao completa da infeccao fungica. Apesar da conduta indicada ter sido a extracao de todos os dentes, o quadro hematologico instavel nao permitiu tais procedimentos, ja que agentes antifibrinoliticos foram considerados insuficientes para controlar a hemorragia e o uso de alfaeptacogue ativado nao foi liberado pelo Ministerio da Saude para realizacao das exodontias. Assim, optou-se pela prescricao de analgesicos e proservacao do caso, enquanto as condicoes hematologicas aguardavam estabilizacao. Esse fato limitou a acao da equipe multiprofissional, uma vez que os focos infecciosos dentarios podem ocasionar episodios de dor intensa e sangramentos espontaneos, agravando ainda mais a condicao geral. O caso demonstra a complexidade do manejo hematologico de um paciente com HAa, levando a dificuldade do tratamento odontologico, nao sendo possivel atender imediatamente as necessidades do paciente mesmo em condicoes onde a intervencao odontologica nao podia ser considerada eletiva. Copyright © 2022

Parvovirus infection causing prolonged QT intervals and cardiac arrest

AimsTo review an unusual case of an infant presenting with parvovirus infection causing prolonged QT intervals and cardiac arrest.MethodsWe reviewed the case history of the patient to discuss the presentation, management and progress since admission.ResultsA 14-month-old boy presented with cough and increased work of breathing for 1 day at district general hospital. He had suspected Parvovirus infection (causing slapped cheeks) 10 days ago. Due to worsening respiratory distress he was tried with various non invasive respiratory support. As he was not responding, he was intubated and ventilated. He was covered with ceftriaxone and acyclovir. During intubation he developed cardiac arrest requiring chest compressions,1 dose of adrenaline and a normal saline bolus. Return of spontaneous circulation happened after 2 minutes. He was transferred to tertiary unit for continuation of care. 2D ECHO showed normal cardiac structure with normal coronary arteries, but markedly dilated left ventricle, left atrium with left ventricular ejection fraction 30%. His was supported with milrinone and adrenaline as inotropes. He was transferred to quaternary centre in view of ECG changes of prolonged QT interval (600msec) global T wave inversion, broad based T wave, poor R wave progression across precordial leads. He was admitted there for 3 weeks before getting discharged to DGH. He received aspirin, bisoprolol, captopril, magnesium strycophosphate, furosemide, spironolactone, lactulose, melatonin, nystatin. After discharge at 1month follow up LVEF was 35%. His NT proBNP peaked to 35000pg/ml during intensive care admission which subsequently normalised to 3000. At discharge QT interval normalised to 480 msec with normal T wave morphology. 24-hour Holter showed sinus rhythm and inverted T waves. Blood cultures showed staphylococcus aureus for which he received 14 days of IV flucloxacillin. His respiratory secretions showed enterovirus, adenovirus and coronavirus 63. His acute kidney injury also resolved. He had normal EEG. His genetic tests for mitochondrial DNA WLS panel and family (parents’ and sibling) genetic tests for prolonged QT were normal. He was seen at cardiac function clinic and inherited arrythmia clinic and diuretics and beta blockers were stopped. Follow up plan about phenotypic exercise testing at later age and avoiding medications causing prolonged QT interval was agreed.ConclusionParvovirus infection can cause transient prolongation of QT interval which can precipitate cardia arrest. In these rare events supporting the child through the acute phase of illness ensures gradual recovery and improvement of the QT prolongation. Currently its not understood as to why this happens but could be postulated to an underlying myocarditis or inflammatory event causing changes in the conducting systems.

Cutaneous thrombosis associated with skin necrosis following Oxford/AstraZeneca COVID-19 vaccination: a case report

A 73-year-old man presented with left shin ulceration two weeks after receiving his first dose of the Oxford-AstraZeneca vaccine. Within 24 h of vaccination, the patient became generally unwell with fever and headache. On the third day after vaccination, he developed left shin erythema and blistering, which rapidly ulcerated. This formed two superficial ulcers with a necrotic base and a violaceous edge on the lateral aspect of his left shin, measuring approximately 2 cm × 3 cm. He had a background of atrial fibrillation and ischemic cardiomyopathy, and had been on several longstanding medications including apixaban. Blood tests revealed normal clotting, full blood count, liver and renal function. The differential diagnosis included pyoderma gangrenosum, vasculitic ulceration, and a cutaneous adverse drug reaction to vaccination. A punch biopsy was obtained from the edge of an ulcer, which revealed microthrombi within blood vessels, an ischemic epidermis, and fat necrosis of subcutaneous tissue. The patient experienced slow healing of ulceration with topical clobetasol propionate 0.05%, neomycin sulphate and nystatin ointment, and compression bandaging treatment. To our knowledge, this is the first reported case of cutaneous thrombosis associated with skin necrosis following Oxford/AstraZeneca vaccination. Recently there have been concerns related to reports of thrombotic events at atypical sites (including cerebral and splanchnic vascular beds) associated with thrombocytopenia following Oxford/ AstraZeneca vaccination (Greinacher A, Thiele T, Warkentin TE et al. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med 2021;384: 2092-101). These findings extend the range of atypically located thromboses associated with COVID-19 vaccination and reinforce the necessity for physicians to be vigilant for signs and symptoms related to thromboses at atypical sites in recently vaccinated patients.

Streptomyces BAC Cloning of a Large-Sized Biosynthetic Gene Cluster of NPP B1, a Potential SARS-CoV-2 RdRp Inhibitor.

As valuable antibiotics, microbial natural products have been in use for decades in various fields. Among them are polyene compounds including nystatin, amphotericin, and nystatin-like Pseudonocardia polyenes (NPPs). Polyene macrolides are known to possess various biological effects, such as antifungal and antiviral activities. NPP A1, which is produced by Pseudonocardia autotrophica, contains a unique disaccharide moiety in the tetraene macrolide backbone. NPP B1, with a heptane structure and improved antifungal activity, was then developed via genetic manipulation of the NPP A1 biosynthetic gene cluster (BGC). Here, we generated a Streptomyces artificial chromosomal DNA library to isolate a large-sized NPP B1 BGC. The NPP B1 BGC was successfully isolated from P. autotrophica chromosome through the construction and screening of a bacterial artificial chromosome (BAC) library, even though the isolated 140-kb BAC clone (named pNPPB1s) lacked approximately 8 kb of the right-end portion of the NPP B1 BGC. The additional introduction of the pNPPB1s as well as co-expression of the 32-kb portion including the missing 8 kb led to a 7.3-fold increase in the production level of NPP B1 in P. autotrophica. The qRT-PCR confirmed that the transcription level of NPP B1 BGC was significantly increased in the P. autotrophica strain containing two copies of the NPP B1 BGCs. Interestingly, the NPP B1 exhibited a previously unidentified SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibition activity in vitro. These results suggest that the Streptomyces BAC cloning of a large-sized, natural product BGC is a valuable approach for titer improvement and biological activity screening of natural products in actinomycetes.

Risk Factors of Oropharyngeal Candidiasis in COVID-19 Patients: A Case-control Study

Background: With the emergence and spread of coronavirus disease 2019 (COVID-19) globally, health care systems have faced the biggest challenge in recent decades. Objectives: The present study aimed to identify risk factors associated with oropharyngeal candidiasis (OPC) in COVID-19 patients. Methods: The total number of confirmed COVID-19 patients was 218 (105 cases with OPC and 113 controls without OPC). The questionnaire used in this study consisted of demographic data, treatment strategy, clinical and laboratory data, and underlying diseases collected from the onset of clinical OPC until the end of hospitalization. Results: Pseudomembranous candidiasis (77/105, 73.3%) was the most prevalent form of OPC in case patients. The majority of the cases (58.1%) and controls (58.4%) were males. Increasing age (P = 0.03) and hospitalization length (P = 0.016) were significantly associated with OPC in COVID-19 patients. Diabetes (P = 0.003), solid tumor (P = 0.019), and hypertension (P = 0.000) were the most common underlying conditions. The use of dentures (P = 0.003) and poor oral hygiene (P = 0.000) were related to OPC in the case group. Therapy with chloroquine (P = 0.012), IVIG (P = 0.001), diuretics (P = 0.000), and corticosteroid pulse therapy (P = 0.000) were significantly associated with developing OPC in case patients. Conclusions: Old age, hospitalization length, poor oral hygiene, corticosteroids use, diabetes, solid tumor, and hypertension may predispose COVID-19 patients to develop OPC. © 2021, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.