Air- and dustborne fungi in repositories of the National Archive of the Republic of Cuba. Borrego S, Vivar I, Molina A. Microb Cell. 2022 Apr 1.
This study has as objectives to determine the concentration and diversity of the air- and dustborne mycobiota in seven National Archive of the Republic of Cuba repositories, and to assess the potential risk of biodeterioration that isolated taxa may have. In the indoor and outdoor environmental microbiological samplings, a SAS biocollector was used and the indoor/outdoor (I/O) ratio was determined for each repository. The settled dust was collected during six months. Sørensen’s coefficient of similarity (QS) was calculated to compare the isolated taxa among the three studied niches (indoor air, dust, outdoor air). The biodegradation potential of the isolated taxa was determined by semi-quantitative tests. The concentrations in the air of repositories with natural cross-ventilation ranged from 225.2-750.3 CFU m-3 , while in the Map library with air-conditioning the concentration was significantly lower. The I/O ratios ranged from 0.1-1.7 revealing different environmental qualities. The maximum settled dust load was 22.8 mg/m2 /day with a top fungal concentration of 6000 CFU g-1. 14 and eleven genera were detected in the air and dust respectively with predominance of the genera Aspergillus, Cladosporium and Penicillium. A QS of 0.8 was obtained between the indoor and the outdoor environments with eleven taxa similar evidencing the incidence of outdoors on the indoor mycobiota. The isolated taxa showed several biodeteriogenic attributes highlighting twelve and 14 taxa from indoor air and dust respectively with positive results for the five tests performed. This demonstrates the potential risk that fungal environmental represent for the preserved documentary heritage.
A recombinant SARS-CoV-2 receptor-binding domain expressed in an engineered fungal strain of Thermothelomyces heterothallica induces a functional immune response in mice. Lazo L, Bequet-Romero M, Lemos G, Musacchio A, Cabrales A, Bruno AJ, et al. Vaccine. 2022 Jan 19;S0264-410X(22)00021-4. https://doi.org/10.1016/j.vaccine.2022.01.007. Online ahead of print.
Since the beginning of the COVID-19 pandemic, the development of effective vaccines against this pathogen has been a priority for the scientific community. Several strategies have been developed including vaccines based on recombinant viral protein fragments. The receptor-binding domain (RBD) in the S1 subunit of S protein has been considered one of the main targets of neutralizing antibodies. In this study we assess the potential of a vaccine formulation based on the recombinant RBD domain of SARS-CoV-2 expressed in the thermophilic filamentous fungal strain Thermothelomyces heterothallica and the hepatitis B virus (HBV) core protein. Functional humoral and cellular immune responses were detected in mice. To our knowledge, this is the first report on the immune evaluation of a biomedical product obtained in the fungal strain T. heterothallica. These results together with the intrinsic advantages of this expression platform support its use for the development of biotechnology products for medical purpose.
Bacterial metalo-aminopeptidases as targets in human infectious diseases. González-Bacerio J, Varela AC, Aguado ME, Izquierdo M, Méndez Y, Del Rivero MA, et al. Curr Drug Targets. 2022 Mar 16. https://doi.org/10.2174/1389450123666220316085859. Online ahead of print.
Background Human infectious diseases caused by bacteria are a worldwide health problem due to the increased resistance of these microorganisms to conventional antibiotics. For this reason, the identification of novel molecular targets and the discovery of new antibacterial compounds is urgently required. Metalo-aminopeptidases are promising targets in bacterial infections. They participate in crucial processes for bacterial growth and pathogenesis, such as protein and peptide degradation to supply amino acids, protein processing, access to host tissues, cysteine supply for redox control, transcriptional regulation, site-specific DNA recombination, and hydrogen sulfide production. Although several of these enzymes are not essential, they are required for virulence and maximal growth in conditions of nutrient limitation and high temperatures. Objective In this review, we describe the structural, functional and kinetic properties of some examples of bacterial metalo-aminopeptidases, in the context of their use as antibacterial targets. In addition, we present some inhibitors reported for these enzymes. Conclusion It is necessary a meticulous work to validate these peptidases as good/bad targets and to identify inhibitors with a potential therapeutic use.
Barriers to Access to Surgery in Patients over 50 Years of Age, Diagnosed with Cataract and Its Visual Effects. Hernández Silva JR, Aguirre Oramas J, Padilla González CM, Hernández Ramos H, Ramos López M. Reports. 2022 Mar 29;2(1):37–42. https://doi.org/10.11648/j.reports.20220201.16
Cataract is the main cause of visual impairment in all regions of the world, which increases with population aging, and its control has been unsuccessful to date, as has been shown by blindness surveys carried out to date, where they have been identified among other aspects the barriers that impede the access of patients to surgical treatment. A prospective longitudinal descriptive study was carried out with the aim of analyzing the barriers to access to surgery in patients older than 50 years, with a diagnosis of cataract and their visual deficit. 121 patients (195 eyes) who met the inclusion criteria and received surgical treatment from January to December 2019 at the ICO “Ramón Pando Ferrer” were selected. The variables studied were age, sex and best corrected visual acuity before and after surgery, personal and ocular pathological history, as well as the barriers that delayed or prevented surgery. Female patients between 70 and 79 years of age predominated, and all the variables studied improved after surgery. Concluding that the barriers to access to cataract surgery identified in this study do not differ from those reported by other regional studies, and indicates that health actions must be carried out between the different levels of medical care, to develop satisfactory prevention blindness policies.
Basal cisternostomy for traumatic brain injury: A case report of unexpected good recovery. Encarnación Ramirez MJ, Barrientos CastilloRE, Vorobiev A, Kiselev N, Álvarez A, Efe IE. Chin J Traumatol. 2021 Dec 28;S1008-1275(21)00208-X. https://doi.org/10.1016/j.cjtee.2021.12.008. Online ahead of print.
In subarachnoid hemorrhage following traumatic brain injury (TBI), the high intracisternal pressure drives the cerebrospinal fluid into the brain parenchyma, causing cerebral edema. Basal cisternostomy involves opening of the basal cisterns to atmospheric pressure and draining cerebrospinal fluid in an attempt to reverse the edema. We describe a case of basal cisternostomy combined with decompressive craniectomy. A 35-year-old man with severe TBI following a road vehicle accident presented with acute subdural hematoma, Glasgow coma scale score of 6, fixed pupils and no corneal response. Opening of the basal cisterns and placement of a temporary cisternal drain led to immediate relaxation of the brain. The patient had a Glasgow coma scale score of 15 on postoperative day 6 and was discharged on day 10. We think basal cisternostomy is a feasible and effective procedure that should be considered in the management of TBI. In subarachnoid hemorrhage following traumatic brain injury (TBI), the high intracisternal pressure drives the cerebrospinal fluid into the brain parenchyma, causing cerebral edema. Basal cisternostomy involves opening of the basal cisterns to atmospheric pressure and draining cerebrospinal fluid in an attempt to reverse the edema. We describe a case of basal cisternostomy combined with decompressive craniectomy. A 35-year-old man with severe TBI following a road vehicle accident presented with acute subdural hematoma, Glasgow coma scale score of 6, fixed pupils and no corneal response. Opening of the basal cisterns and placement of a temporary cisternal drain led to immediate relaxation of the brain. The patient had a Glasgow coma scale score of 15 on postoperative day 6 and was discharged on day 10. We think basal cisternostomy is a feasible and effective procedure that should be considered in the management of TBI.
Blocking EGFR with nimotuzumab: a novel strategy for COVID-19 treatment. Díaz Londres H, Jiménez Armada J, Hernández Martínez A, Abdo Cuza AA, Hernández Sánchez Y, Granado Rodríguez A, et al. Immunotherapy. 2022 Mar 21;10.2217/imt-2022-0027. https://doi.org/10.2217/imt-2022-0027. Online ahead of print.
Background Lung injury and STAT1 deficit induce EGFR overexpression in SARS-CoV-2 infection. Patients & methods A phase I/II trial was done to evaluate the safety and preliminary effect of nimotuzumab, an anti-EGFR antibody, in COVID-19 patients. Patients received from one to three infusions together with other drugs included in the national guideline. Results 41 patients (31 severe and 10 moderate) received nimotuzumab. The median age was 62 years and the main comorbidities were hypertension, diabetes and cardiovascular disease. The antibody was very safe and the 14-day recovery rate was 82.9%. Inflammatory markers decreased over time. Patients did not show signs of fibrosis. Conclusion Nimotuzumab is a safe antibody that might reduce inflammation and prevent fibrosis in severe and moderate COVID-19 patients.
Chitosan/Pluronic F127 Thermosensitive Hydrogel as an Injectable Dexamethasone Delivery Carrier. García-Couce J, TomásM, FuentesG, Que I, Almirall A, Cruz LJ. Gels. 2022 Jan 7;8(1):44. https://doi.org/10.3390/gels8010044
Intra-articular administration of anti-inflammatory drugs is a strategy that allows localized action on damaged articular cartilage and reduces the side effects associated with systemic drug administration. The objective of this work is to prepare injectable thermosensitive hydrogels for the long-term application of dexamethasone. The hydrogels were prepared by mixing chitosan (CS) and Pluronic-F127 (PF) physically. In addition, tripolyphosphate (TPP) was used as a crosslinking agent. Chitosan added to the mix increased the gel time compared to the pluronic gel alone. The incorporation of TPP into the material modified the morphology of the hydrogels formed. Subsequently, MTS and Live/Dead® experiments were performed to investigate the toxicity of hydrogels against human chondrocytes. The in vitro releases of dexamethasone (DMT) from CS-PF and CS-PF-TPP gels had an initial burst and took more time than that from the PF hydrogel. In vivo studies showed that hydrogels retained the fluorescent compound longer in the joint than when administered in PBS alone. These results suggest that the CS-PF and CS-PF-TPP hydrogels loaded with DMT could be a promising drug delivery platform for the treatment of osteoarthritis.
Comparison of in vitro anti-Staphylococcus aureus activity of eight antibiotics and four dilutions of propolis. Fernández León KJ, Rodríguez Díaz JA, Reyes Espinosa L, Duquesne Alderete A, Solenzal Valdivia YO, Rives Quintero A. J Selva Andina Res Soc. 2022 Feb;13(1):35–48. https://doi.org/10.36610/j.jsars.2022.130100035
The objective of this research was based on the comparison of inhibition halos of a sample of Staphylococcus aureus, faced in vitro with eight antibiotics used in medicine, as well as four alcoholic concentrations of propolis. The results indicate that the antimicrobial action of propolis, depending on the bioactive compounds such as: flavonoids, polyphenols, aromatic acids, etc., contained in this product. The antibacterial activity of the four propolis dilutions produced inhibition halos between 10 and 20 mm. Of the eight antibiotics with which the comparison was made, only erythromycin was found to be resistant to S. aureus. Penicillin produced halos with smaller dimensions. Although the halos derived from the rest of the antimicrobials were greater than those from propolis, many of them were found within the range originated by said product from the hive. Compared antibacterial resistance has not been demonstrated, with which over the year’s antibiotics present, when used indiscriminately to eliminate or control antimicrobial agents.
Computed tomography angiography versus Agatston score for diagnosis of coronary artery disease in patients with stable chest pain: individual patient data meta-analysis of the international COME-CCT Consortium. Wieske V, Walther M, Dubourg B, Alkadhi H, Nørgard BL, Meijs MFL, et al. Eur Radiol. 2022 Mar 10. https://doi.org/10.1007/s00330-022-08619-4. Online ahead of print.
Objectives There is conflicting evidence about the comparative diagnostic accuracy of the Agatston score versus computed tomography angiography (CTA) in patients with suspected obstructive coronary artery disease (CAD). Purpose To determine whether CTA is superior to the Agatston score in the diagnosis of CAD. Methods In total 2452 patients with stable chest pain and a clinical indication for invasive coronary angiography (ICA) for suspected CAD were included by the Collaborative Meta-analysis of Cardiac CT (COME-CCT) Consortium. An Agatston score of > 400 was considered positive, and obstructive CAD defined as at least 50% coronary diameter stenosis on ICA was used as the reference standard. Results Obstructive CAD was diagnosed in 44.9% of patients (1100/2452). The median Agatston score was 74. Diagnostic accuracy of CTA for the detection of obstructive CAD (81.1%, 95% confidence interval [CI]: 77.5 to 84.1%) was significantly higher than that of the Agatston score (68.8%, 95% CI: 64.2 to 73.1%, p < 0.001). Among patients with an Agatston score of zero, 17% (101/600) had obstructive CAD. Diagnostic accuracy of CTA was not significantly different in patients with low to intermediate (1 to < 100, 100-400) versus moderate to high Agatston scores (401-1000, > 1000). Conclusions Results in our international cohort show CTA to have significantly higher diagnostic accuracy than the Agatston score in patients with stable chest pain, suspected CAD, and a clinical indication for ICA. Diagnostic performance of CTA is not affected by a higher Agatston score while an Agatston score of zero does not reliably exclude obstructive CAD.
DELOS Nanovesicles-Based Hydrogels: An Advanced Formulation for Topical Use. Ballell-HosaL, González-Mira E, Santana H, Morla-Folch J, Moreno-Masip M, Martínez-Prieto Y, et al. Pharmaceutics. 2022 Jan 15;14(1):199. https://doi.org/10.3390/pharmaceutics14010199
Topical delivery has received great attention due to its localized drug delivery, its patient compliance, and its low risk for side effects. Recent developments have focused on studying new drug delivery systems as a strategy for addressing the challenges of current topical treatments. Here we describe the advances on an innovative drug delivery platform called DELOS nanovesicles for topical drug delivery. Previously, the production of DELOS nanovesicles demonstrated potentiality for the topical treatment of complex wounds, achieving well-tolerated liquid dispersions by this route. Here, research efforts have been focused on designing these nanocarriers with the best skin tolerability to be applied even to damaged skin, and on exploring the feasibility of adapting the colloidal dispersions to a more suitable dosage form for topical application. Accordingly, these drug delivery systems have been efficiently evolved to a hydrogel using MethocelTM K4M, presenting proper stability and rheological properties. Further, the integrity of these nanocarriers when being gellified has been confirmed by cryo-transmission electron microscopy and by Förster resonance energy transfer analysis with fluorescent-labeled DELOS nanovesicles, which is a crucial characterization not widely reported in the literature. Additionally, in vitro experiments have shown that recombinant human Epidermal Growth Factor (rhEGF) protein integrated into gellified DELOS nanovesicles exhibits an enhanced bioactivity compared to the liquid form. Therefore, these studies suggest that such a drug delivery system is maintained unaltered when hydrogellified, becoming the DELOS nanovesicles-based hydrogels, an advanced formulation for topical use.
Early Protein Energy Malnutrition impacts life-long developmental trajectories of the sources of EEG rhythmic activity. Bosch-Bayard J, Razzaq FA, López-NaranjoC, WangY, Li M, Galán-García L, et al. Neuroimage. 2022 Mar 24;119144. https://doi.org/10.1016/j.neuroimage.2022.119144. Online ahead of print.
Protein Energy Malnutrition (PEM) has lifelong consequences on brain development and cognitive function. We studied the lifelong developmental trajectories of resting-state EEG source activity in 66 individuals with histories of Protein Energy Malnutrition (PEM) limited to the first year of life and in 83 matched classmate controls (CON) who are all participants of the 49 years longitudinal Barbados Nutrition Study (BNS). qEEGt source z-spectra measured deviation from normative values of EEG rhythmic activity sources at 5-11 years of age and 40 years later at 45-51 years of age. The PEM group showed qEEGt abnormalities in childhood, including a developmental delay in alpha rhythm maturation and an insufficient decrease in beta activity. These profiles may be correlated with accelerated cognitive decline.
Evaluation of Subcutaneous Immunotherapy in Asthmatics to Dermatophagoides Siboney and Dermatophagoides Pteronyssinus. Castro Almarales RL, Ronquillo Díaz M, Álvarez Castelló M, Rodríguez Canosa J, González Léon M, Enríquez Domínguez I, et al. Int J Clin Med Allergy. 2022 Jan 28;7(1):73–80.
DOI: http://dx.doi.org/10.19070/2332-2799-2200014 [No abstract available]
Extraventricular Choroidal Plexus papilloma. Report of One Case. Lacerda Gallardo AJ, Abreu Pérez D, Gálvez JA. J Neurosci Neurosurg. 2022 Mar 8;5(1):154. https://doi.org/10.31021/jnn.20225156
Choroid plexus tumors are primary neoplasms of the central nervous system, of neuroectodermal origin. In children they have a special predilection for the lateral ventricles and the third ventricle, while in adults they are more frequently located in the fourth ventricle. The location of this tumor outside the ventricular cavity is rare butit can be located in brain parenchyma, in the brainstem, in the suprasellar region or even in the spinal canal. We are showing an ectopic location of a choroid plexus papilloma in a young female patient who underwent surgery in the Neurosurgery service of the General Teaching Hospital “Roberto Rodríguez” in Morón, Ciego de Ávila, Cuba.
First Report on Microcystin-LR Occurrence in Water Reservoirs of Eastern Cuba, and Environmental Trigger Factors. Rodríguez Tito JC, Gómez Luna LM, Noppe Noppe W, Alvarez Hubert I. Toxins. 2022 Mar 15;14(3):209. https://doi.org/10.3390/toxins14030209
The factors related to cyanotoxin occurrence and its social impact, with comprehension and risk perception being the most important issues, are not yet completely understood in the Cuban context. The objectives of this research were to determine the risk extension and microcystin-LR levels, and to identify the environmental factors that trigger the toxic cyanobacteria growth and microcystin-LR occurrence in 24 water reservoirs in eastern Cuba. Samplings were performed in the early morning hours, with in situ determination and physicochemical analysis carried out in the laboratory. Microcystin-LR were determined in water and within the cells (intracellular toxins) using UPLC–MS analysis after solid phase extraction. The reservoirs studied were found to be affected by eutrophication, with high levels of TN:TP ratio and phytoplankton cell concentrations, high water temperatures and low transparency, which cause collateral effect such as cyanobacterial bloom and microcystin-LR occurrence. In Hatillo, Chalóns, Parada, Mícara, Baraguá, Cautillo, La Yaya, Guisa and Jaibo reservoirs, concentrations of MC-LR higher than the WHO limits for drinking water (1 µg·L−1), were detected.
Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It? Robinson-Agramonte MA, Noris García E, Fraga Guerra J, Vega Hurtado Y, Antonucci N, et al. Int J Mol Sci . 2022 Mar 11;23(6):3033. https://doi.org/10.3390/ijms23063033
Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental disorders characterized by a wide and variable set of neuropsychiatric symptoms, including deficits in social communication, narrow and restricted interests, and repetitive behavior. The immune hypothesis is considered to be a major factor contributing to autism pathogenesis, as well as a way to explain the differences of the clinical phenotypes and comorbidities influencing disease course and severity. Evidence highlights a link between immune dysfunction and behavioral traits in autism from several types of evidence found in both cerebrospinal fluid and peripheral blood and their utility to identify autistic subgroups with specific immunophenotypes; underlying behavioral symptoms are also shown. This review summarizes current insights into immune dysfunction in ASD, with particular reference to the impact of immunological factors related to the maternal influence of autism development; comorbidities influencing autism disease course and severity; and others factors with particular relevance, including obesity. Finally, we described main elements of similarities between immunopathology overlapping neurodevelopmental and neurodegenerative disorders, taking as examples autism and Parkinson Disease, respectively.
Ligand-based discovery of new potential acetylcholinesterase inhibitors for Alzheimer’s disease treatment. Cañizares-Carmenate Y, Nam N-H, Díaz-Amador R, Thuan NT, Dung PTP, Torrens F, et al. SAR QSAR Environ Res. 2022 Jan;33(1):49–61. https://doi.org/10.1080/1062936X.2022.2025615. Epub 2022 Jan 20.
The enzyme acetylcholinesterase (AChE) is currently a therapeutic target for the treatment of neurodegenerative diseases. These diseases have highly variable causes but irreversible evolutions. Although the treatments are palliative, they help relieve symptoms and allow a better quality of life, so the search for new therapeutic alternatives is the focus of many scientists worldwide. In this study, a QSAR-SVM classification model was developed by using the MATLAB numerical computation system and the molecular descriptors implemented in the Dragon software. The obtained parameters are adequate with accuracy of 88.63% for training set, 81.13% for cross-validation experiment and 81.15% for prediction set. In addition, its application domain was determined to guarantee the reliability of the predictions. Finally, the model was used to predict AChE inhibition by a group of quinazolinones and benzothiadiazine 1,1-dioxides obtained by chemical synthesis, resulting in 14 drug candidates with in silico activity comparable to acetylcholine.
Modeling and prediction of dengue cases in the short and long term in Villa Clara, Cuba using climatic variables and objective regressive regression. Campos Sánchez CM, Guillén León LA, del Valle Laveaga D, Acosta Escanaverino I, Rodríguez Hurtado D, Osés Rodríguez R. GSC Biol Pharma Sci. 2022 Mar 3;18(3):35–45. https://doi.org/10.30574/gscbps.2022.18.3.0090
Climate has an important influence on infectious diseases and their different modes of transmission. Dengue is among the most relevant for Cuban public health. Due to the pronounced effect that environmental changes can have on the biology of Aedes aegypti, it is very likely that the epidemiology of this arbovirosis will be profoundly influenced by future climate change. The aim of the study was to analyze the possible relationship between meteorological variables and the incidence of Dengue in Villa Clara province, Cuba during the years 2017-2020, and to perform a predictive model of the behavior of the disease during 2021. Retrospective research was carried out in which the possible effects of diversifications of temperature, precipitation, humidity, water vapor tension, atmospheric pressure, wind speed, cloudiness and saturation deficit on the deviations in the epidemiological curves of Dengue infection in Villa Clara (2017-2020) were analyzed to predict the future behavior of the referred entity during the current year. A correlation of the infectious entity with minimum temperature (R=0.332; p=0.023) and water vapor tension (R=0.298; p=0.042) was obtained, as well as an inverse relationship with atmospheric pressure (R=-0.317; p=0.030). It is concluded that a predictive model was obtained for 2021 with high reliability, in which a decrease in the incidence of Dengue is predicted in the month of March until July, but after August to December the values will increase greatly.
Mucosal and systemic immune responses following mucosal immunisation of tetanus toxoid entrapped in lipid nanoparticles prepared by microwave reactor. Gebril A, Obeid MA, BennettEM, Pujol A, Chovel ML, Mahy T, et al. Eur J Pharm Biopharm. 2022 Jan 3;S0939-6411(21)00363-5. https://doi.org/10.1016/j.ejpb.2021.12.014. Online ahead of print.
In this study, the use of a microwave reactor, which allowed high input of energy into a pressurised system in a short period of time, was investigated for preparation of lipid nanoparticles (LNPs). The aim was to optimise the formulation process by reducing manufacturing time. Two types of LNPs were prepared; non-ionic surfactant vesicles (NISV) and bilosomes (modified NISV incorporating bile salts), with a model antigen (tetanus toxoid, TT) and the immune response induced after mucosal (nasal and oral, respectively) administration was assessed. The TT loaded LNPs were characterised in terms of particle size, size distribution, morphology, and entrapment efficiency. Immunisation was evaluated by lethal challenge with tetanus toxin in an animal model. The efficiency of vaccination was evaluated by measuring the anti-TT IgG antibody levels in the vaccinated animals. Bilosomes formed by this method showed an immunogen entrapment efficiency of ∼ 30% which was significantly (p<0.05) higher than entrapment efficiency in the NISV. The percentage of animals that survived when challenged with tetanus toxin correlated with the level of IgG determined in the serum of mice immunised with LNPs by the mucosal route. Moreover, there were significant (p<0.05) differences between orally and nasally immunised groups. Animal groups immunised bilosomes via the oral route showed the highest level of IgG (1.2±0.13) compared to the positive control, LN+Xn, and no immunised group. Similarly, groups immunised via the nasal route showed significantly (p<0.0001) higher titres compared with the control group. Mucosal TT was capable of inducing systemic specific IgG anti-TT responses that were higher than the parenteral vaccine.
Multilocus Genotyping of Pneumocystis jirovecii from Deceased Cuban AIDS Patients Using Formalin-Fixed and Paraffin-Embedded Tissues. Friaza V, de Armas Y, Capó V, Morilla R, Plascencia-Hernández A, Pérez-Gómez HR. J Fungi (Basel). 2021 Dec 5;7(12):1042. https://doi.org/10.3390/jof7121042
The results of the genotypic characterization of Pneumocystis jirovecii are described in lung tissue samples from 41 Cubans who died of AIDS with pneumocystosis between 1995 and 2008. Histological sections of the lung preserved as formalin-fixed and paraffin-embedded tissue were examined. PCR amplification and nucleotide sequencing of the two mitochondrial genes (large and small) of the pathogen allowed verification of a predominance of genotype 3 (85T/248C) of the large mitochondrial gene and genotype 3 (160A/196T) of the small mitochondrial gene over a period of 14 years (1995-2008). These results suggest that the 85T/248C//160A/196T genotype circulates with the highest frequency (81.3%) among AIDS patients in Cuba. Multilocus analysis indicates a limited circulation of pathogen genotypes on the island with the existence of a clonal genotype with an epidemic structure. Furthermore, it appears that circulating strains of P. jirovecii have not developed mutations related to sulfonamide resistance. Taken together, the data in this study revealed important elements about pneumocystosis in Cuban patients dying of AIDS and the usefulness of formalin-fixed and paraffin-embedded samples to carry out molecular epidemiology studies of P. jirovecii.
Open Label, Evaluation of the effects of the uncontrolled use of Biomodulina T on the severity of SARS-CoV-2 infections in older Cuban Adults. Cañete R, Afonso JA, Brito K. Curr Ther Res Clin Exp. 2022 Jan 12;100662. https://doi.org/10.1016/j.curtheres.2022.100662. Online ahead of print.
Background The ongoing Covid-19 pandemic is a worldwide public health threat. Millions of people are at risk and older adults are more susceptible to developing the most serious manifestations of the disease, in part because the ageing of the immune system. Biomodulina T® is an injectable immune modulator that has been licensed for use in Cuba for many years. An open-label, uncontrolled trial was conducted to investigate whether it might be useful to prevent or modulate the serious effects of SARS-CoV-2 infections in older Cuban adults prior to the availability of vaccinations. Methods From April 12 to August 31, 2021, 1239 adults, sixty years and older, unvaccinated against COVID-19 were recruited from the José Luis Dubrocq polyclinics, to receive Biomodulina T®, one intramuscular 3 ml dose weekly for 6 weeks. Each person was visited at home weekly to be given Biomodulina T®. Once daily subjects were seen by a medical student to collect information on any possible adverse events related to the medication as well as any symptoms of COVID-19. The possible usefulness of the intervention and its potential adverse events were assessed based on the number of older adults who became infected with COVID-19, and the severity of any symptoms reported or noted both during the 6-week treatment period and during an additional 6 week post-treatment observation period. Results Sixteen subjects were diagnosed with symptomatic COVID-19 during the intervention using a specific RT-PCR. One subject died because of COVID-19. The most common pre-existing diagnoses in treated subjects included High Blood Pressure in 64.8%, Diabetes Mellitus in 19.85%, and Ischemic Cardiopathy in 13.88%. Biomodulina T® was well tolerated. Only infrequent, mild, transient, and self-limited adverse events were identified. Both the incidence of COVID-19 infections and the overall mortality rate were lower in the treated subjects than what was observed in the untreated general population of this Cuban province during the same time period. Conclusion While further, confirmatory, double-blind, controlled clinical trials are needed, Biomodulina T® injections were well tolerated, and the results of this open, uncontrolled study suggest that it may have been useful to decrease the incidence and severity of symptomatic SARS-CoV-2 infections in these older Cuban adults.
Polyphosphazene-Based Nanocarriers for the Release of Camptothecin and Epirubicin. Pérez Quiñones J, Roschger C, Iturmendi A, Henke H, Zierer A, Peniche-Covas C, et al. Pharmaceutics. 2022 Jan 11;14(1):169. https://doi.org/10.3390/pharmaceutics14010169
The design and study of efficient polymer-based drug delivery systems for the controlled release of anticancer drugs is one of the pillars of nanomedicine. The fight against metastatic and invasive cancers demands therapeutic candidates with increased and selective toxicity towards malignant cells, long-term activity and reduced side effects. In this sense, polyphosphazene nanocarriers were synthesized for the sustained release of the anticancer drugs camptothecin (CPT) and epirubicin (EPI). Linear poly(dichloro)phosphazene was modified with lipophilic tocopherol or testosterone glycinate, with antioxidant and antitumor activity, and with hydrophilic Jeffamine M1000 to obtain different polyphosphazene nanocarriers. It allowed us to encapsulate the lipophilic CPT and the more hydrophilic EPI. The encapsulation process was carried out via solvent exchange/precipitation, attaining a 9.2-13.6 wt% of CPT and 0.3-2.4 wt% of EPI. CPT-loaded polyphosphazenes formed 140-200 nm aggregates in simulated body physiological conditions (PBS, pH 7.4), resulting in an 80-100-fold increase of CPT solubility. EPI-loaded polyphosphazenes formed 250 nm aggregates in an aqueous medium. CPT and EPI release (PBS, pH 7.4, 37 °C) was monitored for 202 h, being almost linear during the first 8 h. The slow release of testosterone and tocopherol was also sustained for 150 h in PBS (pH 7.4 and 6.0) at 37 °C. The co-delivery of testosterone or tocopherol and the anticancer drugs from the nanocarriers was expected. Cells of the human breast cancer cell line MCF-7 demonstrated good uptake of anticancer-drug-loaded nanocarriers after 6 h. Similarly, MCF-7 spheroids showed good uptake of the anticancer-drug-loaded aggregates after 72 h. Almost all anticancer-drug-loaded polyphosphazenes exhibited similar or superior toxicity against MCF-7 cells and spheroids when compared to raw anticancer drugs. Additionally, cell-cycle arrest in the G2/M phase was increased in response to the drug-loaded nanocarriers. Almost no toxicity of anticancer-drug-loaded aggregates against primary human lung fibroblasts was observed. Furthermore, the aggregates displayed no hemolytic activity, which is in contrast to the parent anticancer drugs. Consequently, synthesized polyphosphazene-based nanocarriers might be potential nanomedicines for chemotherapy.
Population dynamics of Aedes aegypti (Diptera: Culicidae): Contributions to the prevention of arbovirosis in Villa Clara, Cuba. Fimia Duarte R, Guerra Véliz Y, del Valle Laveaga D, Morales Guerra RJ, Castañeda López W, Leiva Haza J. GSC Biol Pharma Sci. 2022 Feb 12;18(2) :173–88. https://doi.org/10.30574/gscbps.2022.18.2.0066
Emerging and re-emerging infectious diseases constitute one of the main health problems worldwide. The objective of the research consisted of analyzing the development dynamics of adult mosquito populations of the species Ae. aegypti in Villa Clara province, Cuba during the period 2016-2020. The research covered the 13 municipalities of Villa Clara. An observational, descriptive, ecological, retrospective and analytical-statistical (by decision tree/exploratory data analysis) study was conducted. The study was based on the collection of positive samples/number of outbreaks reported in the 13 municipalities of the province, in the different months of the period analyzed, for the mosquito species Ae. aegypti, where each sample point corresponded to the number of specimens collected in one of the years covered, with one of the months of the year in question (12 months), the 13 municipalities, and 9 types of reservoirs. This resulted in 7 020 observations, which constitutes the sample size. The presence of the species under analysis was found in the 13 municipalities of the province, with abundant population densities; on the other hand, the variables with the greatest incidence in the population dynamics were: municipality and type of reservoir, with emphasis on the low tank, as the preferred oviposition and breeding site for this species. It is concluded that Ae. aegypti has a high capacity for adaptation and high e
Prevention of tick-borne diseases: challenge to recent medicine. Hromníková D, Daniel Furka D, Furka S, Dueñas Santana JA, Ravingerová T, Klöcklerová V, et al. Biologia (Bratisl). 2022 Mar 9;1–22. https://doi.org/10.1007/s11756-021-00966-9. Online ahead of print.
Ticks represent important vectors and reservoirs of pathogens, causing a number of diseases in humans and animals, and significant damage to livestock every year. Modern research into protection against ticks and tick-borne diseases focuses mainly on the feeding stage, i.e. the period when ticks take their blood meal from their hosts during which pathogens are transmitted. Physiological functions in ticks, such as food intake, saliva production, reproduction, development, and others are under control of neuropeptides and peptide hormones which may be involved in pathogen transmission that cause Lyme borreliosis or tick-borne encephalitis. According to current knowledge, ticks are not reservoirs or vectors for the spread of COVID-19 disease. The search for new vaccination methods to protect against ticks and their transmissible pathogens is a challenge for current science in view of global changes, including the increasing migration of the human population.
Quantitative NMR for the structural analysis of novel bivalent glycoconjugates as vaccine candidates. Humpierre AR, Zanuy A, Saenz M, Vasco AV, Méndez Y, Westermann B, et al. J Pharm Biomed Anal. 2022 Mar 11;214:114721. https://doi.org/10.1016/j.jpba.2022.114721. Online ahead of print.
Novel unimolecular bivalent glycoconjugates were assembled combining several functionalized capsular polysaccharides of Streptococcus pneumoniae and Neisseria meningitidis to a carrier protein by using an effective strategy based on the Ugi 4-component reaction. The development of multivalent glycoconjugates opens new opportunities in the field of vaccine design, but their high structural complexity involves new analytical challenges. Nuclear Magnetic Resonance has found wide applications in the characterization and impurity profiling of carbohydrate-based vaccines. Eight bivalent conjugates were studied by quantitative NMR analyzing the structural identity, the content of each capsular polysaccharide, the ratios between polysaccharides, the polysaccharide to protein ratios and undesirable contaminants. The qNMR technique involves experiments with several modified parameters for obtaining spectra with quantifiable signals. In addition, the achieved NMR results were combined with the results of colorimetric assay and Size Exclusion HPLC for assessing the protein content and free protein percentage, respectively. The application of quantitative NMR showed to be efficient to clear up the new structural complexities while allowing the quantitative assessment of the components.
Risk factors for head and neck cancer in more and less developed countries: Analysis from the INHANCE Consortium. Goyal N, Hennessy M, Lehman E, Lin W, Agudo A, Ahrens W, et al. Oral Dis. 2022 Mar 24. https://doi.org/10.1111/odi.14196. Online ahead of print.
Objective We analyzed the pooled case-control data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare cigarette smoking and alcohol consumption risk factors for head and neck cancer between less developed and more developed countries. Subjects and methods The location of each study was categorized as either a less developed or more developed country. We compared the risk of overall head and neck cancer and cancer of specific anatomic subsites associated with cigarette smoking and alcohol consumption. Additionally, age and sex distribution between categories was compared. Results The odds ratios for head and neck cancer sites associated with smoking duration differed between less developed and more developed countries. Smoking greater than 20 years conferred a higher risk for oral cavity and laryngeal cancer in more developed countries, whereas the risk was greater for oropharynx and hypopharynx cancer in less developed countries. Alcohol consumed for more than 20 years conferred a higher risk for oropharynx, hypopharynx and larynx cancer in less developed countries. The proportion of cases that were young (<45 years) or female differed by country type for some HNC subsites. Conclusion These findings suggest the degree of industrialization and economic development affects the relationship between smoking-and alcohol with head and neck cancer.
Study protocol for a randomised, double-blinded, placebo-controlled phase III trial examining the add-on efficacy, cost-utility and neurobiological effects of low-dose naltrexone (LDN) in patients with fibromyalgia (INNOVA study). Colomer-Carbonell A, Sanabria-Mazo JP, Hernández-Negrín H, Xavier Borràs X, Suso-Ribera C, García-PalaciosA, et al. BMJ Open. 2022 Jan 6;12(1):e055351. https://doi.org/10.1136/bmjopen-2021-055351
Introduction There is evidence that low-dose naltrexone (LDN; <5.0 mg/day) reduces pain and improves the quality of life of people with fibromyalgia syndrome (FMS). However, no randomised controlled trials with long-term follow-ups have been carried out. The INNOVA study will evaluate the add-on efficacy, safety, cost-utility and neurobiological effects of LDN for reducing pain in patients with FMS, with a 1-year follow-up. Methods and analysis A single-site, prospective, randomised, double-blinded, placebo-controlled, parallel design phase III trial will be performed. Eligibility criteria include being adult, having a diagnosis of FMS and experiencing pain of 4 or higher on a 10-point numerical rating scale. Participants will be randomised to a LDN intervention group (4.5 mg/day) or to a placebo control group. Clinical assessments will be performed at baseline (T0), 3 months (T1), 6 months (T2) and 12 months (T3). The primary endpoint will be pain intensity. A sample size of 60 patients per study arm (120 in total), as calculated prior to recruitment for sufficient power, will be monitored between January 2022 and August 2024. Assessment will also include daily ecological momentary evaluations of FMS-related symptoms (eg, pain intensity, fatigue and sleep disturbance), and side effects via ecological momentary assessment through the Pain Monitor app during the first 3 months. Costs and quality-adjusted life years will be also calculated. Half of the participants in each arm will be scanned with MRI at T0 and T1 for changes in brain metabolites related to neuroinflammation and central sensitisation. Inflammatory biomarkers in serum will also be measured. Ethics and dissemination This study has been approved by the Ethics Committee of the Fundació Sant Joan de Déu. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and community engagement activities.
Targeting of Protein Kinase CK2 Elicits Antiviral Activity on Bovine Coronavirus Infection. Ramón AC, Pérez GV, Caballero E, Rosales M, Aguilar D, Vázquez-Blomquist D, et al. Viruses . 2022 Mar 7;14(3):552. https://doi.org/10.3390/v14030552
Coronaviruses constitute a global threat to the human population; therefore, effective pan-coronavirus antiviral drugs are required to tackle future re-emerging virus outbreaks. Protein kinase CK2 has been suggested as a promising therapeutic target in COVID-19 owing to the in vitro antiviral activity observed after both pharmacologic and genetic inhibition of the enzyme. Here, we explored the putative antiviral effect of the anti-CK2 peptide CIGB-325 on bovine coronavirus (BCoV) infection using different in vitro viral infected cell-based assays. The impact of the peptide on viral mRNA and protein levels was determined by qRT-PCR and Western blot, respectively. Finally, pull-down experiments followed by Western blot and/or mass spectrometry analysis were performed to identify CIGB-325-interacting proteins. We found that CIGB-325 inhibited both the cytopathic effect and the number of plaque-forming units. Accordingly, intracellular viral protein levels were clearly reduced after treatment of BCoV-infected cells, with CIGB-325 determined by immunocytochemistry. Pull-down assay data revealed the physical interaction of CIGB-325 with viral nucleocapsid (N) protein and a group of bona fide CK2 cellular substrates. Our findings evidence in vitro antiviral activity of CIGB-325 against bovine coronavirus as well as some molecular clues that might support such effect. Altogether, data provided here strengthen the rationale of inhibiting CK2 to treat betacoronavirus infections.
Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric Site. Hernández González JE, Alberca LN, Masforrol González Y, Reyes Acosta O, Talevi A, Salas-Sarduy E. J Chem Inf Model. 2022 Jan 10;62(1):159–75. https://doi.org/10.1021/acs.jcim.1c01189. Epub 2021 Dec 28.
Allosteric inhibitors regulate enzyme activity from remote and usually specific pockets. As they promise an avenue for less toxic and safer drugs, the identification and characterization of allosteric inhibitors has gained great academic and biomedical interest in recent years. Research on falcipain-2 (FP-2), the major papain-like cysteine hemoglobinase of Plasmodium falciparum, might benefit from this strategy to overcome the low selectivity against human cathepsins shown by active site-directed inhibitors. Encouraged by our previous finding that methacycline inhibits FP-2 noncompetitively, here we assessed other five tetracycline derivatives against this target and characterized their inhibition mechanism. As previously shown for methacycline, tetracycline derivatives inhibited FP-2 in a noncompetitive fashion, with Ki values ranging from 121 to 190 μM. A possible binding to the S’ side of the FP-2 active site, similar to that described by X-ray crystallography (PDB: 6SSZ) for the noncompetitive inhibitor E-chalcone 48 (EC48), was experimentally discarded by kinetic analysis using a large peptidyl substrate spanning the whole active site. By combining lengthy molecular dynamics (MD) simulations that allowed methacycline to diffuse from solution to different FP-2 surface regions and free energy calculations, we predicted the most likely binding mode of the ligand. Of note, the proposed binding pose explains the low differences in Ki values observed for the tested tetracycline derivatives and the calculated binding free energies match the experimental values. Overall, this study has implications for the design of novel allosteric inhibitors against FP-2 and sets the basis for further optimization of the tetracycline scaffold to produce more potent and selective inhibitors.
The potential diagnostic accuracy of circulating microRNAs for prostate cancer: A meta-analysis. Zhang WT, Zhang GX, Zhao RZ, Gao SS. Actas Urol Esp (Engl Ed). 2022 Mar 5;S2173-5786(22)00009-9. https://doi.org/10.1016/j.acuroe.2021.05.005. Online ahead of print.
Objectives This meta-analysis has been conducted to evaluate the diagnostic accuracy of circulating microRNAs for the early diagnosis of prostate cancer (PCA). Methods A systematic literature search was performed (updated to February 18, 2021) in PubMed, EMBASE, Web of Science, Cochrane Library, Wanfang database and China National Knowledge Infrastructure (CNKI) to identify eligible studies. The pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under curve (AUC) of the summary receiver-operating characteristic (SROC) curve were calculated for both overall and subgroup analysis. The meta-regression and subgroup analysis were performed to explore heterogeneity and Deeks’ funnel plot was used to assess publication bias. Results One hundred nineteen studies from 33 articles owned 8703 PCA patients and 4914 controls were included in our meta-analysis. The overall sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and area under the curve were 0.79, 0.81, 4.1, 0.26, 16 and 0.87, respectively. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve of miR-21 in diagnosis of PCA were 0.86, 0.90, 8.3, 0.16, 52 and 0.94, respectively. Subgroup analysis suggested that the upregulated miRNA of serum type with large sample size could carry out a better diagnostic accuracy of PCA patients. Moreover, publication bias was not found. Conclusions Circulating microRNA, especially miR-21, can be used as a promising noninvasive biomarker in the early diagnosis of PCA.
The Safety and Efficacy of a Therapeutic Vaccine for Chronic Hepatitis B: A Follow-Up Study of Phase III Clinical Trial. Fazle Akbar SM, Al Mahtab M, Aguilar JC, Yoshida O, KhanS, Pentón E, et al. Vaccines (Basel). 2021 Dec 30;10(1):45.
https://doi.org/10.3390/vaccines10010045
The objective of the present study was to assess the safety and efficacy of a therapeutic vaccine containing both HBsAg and HBcAg (NASVAC) in patients with chronic hepatitis B (CHB) three years after the end of treatment (EOT) as a follow-up of a phase III clinical trial. NASVAC was administered ten times by the nasal route and five times by subcutaneous injection. A total of 59 patients with CHB were enrolled. Adverse events were not seen in any of the patients. Out of the 59 CHB patients, 54 patients exhibited a reduction in HBV DNA, compared with their basal levels. Although all the patients had alanine transaminase (ALT) above the upper limit of normal (>42 IU/L) before the commencement of therapy, the levels of ALT were within the ULN level in 42 patients. No patient developed cirrhosis of the liver. The present study, showing the safety and efficacy of NASVAC 3 years after the EOT, is the first to report follow-up data of an immune therapeutic agent against CHB. NASVAC represents a unique drug against CHB that is safe, of finite duration, can be administered by the nasal route, is capable of reducing HBV DNA and normalizing ALT, and contains hepatic fibrosis.
Transdiagnostic alterations in neural emotion regulation circuits – neural substrates of cognitive reappraisal in patients with depression and post-traumatic stress disorder. Keller M, Mendoza-Quiñones R, Cabrera Muñoz A, Iglesias-Fuster J, Valdés Virués A, Zvyagintsev M, et al. BMC Psychiatry. 2022 Mar 8;22(1):173. https://doi.org/10.1186/s12888-022-03780-y
Background Impaired cognitive reappraisal, associated with the social functioning and well-being of patients affected by mood or anxiety disorders, is characterized by distinct neural activation patterns across clinical populations. To date, studies dedicated to identifying common and distinct neural activation profiles need to be clarified. The aim of the present study was to investigate transdiagnostic differences and commonalities in brain activation patterns during reappraisal-mediated downregulation of emotions. Methods Cognitive reappraisal of negative images was contrasted with maintaining emotions during a control viewing condition. Brain activation in 35 patients with major depressive disorder (MDD), 20 patients with post-traumatic stress disorder (PTSD), and 34 healthy controls (HC) during cognitive reappraisal was compared. Moreover, the neural circuitry of emotion regulation in these clinical populations was examined using seed-to-voxel and voxel-to-voxel functional connectivity analyses. Results Whole-brain fMRI analyses showed less right-lateralized activation of the inferior, middle, and superior frontal gyrus during cognitive reappraisal compared to viewing of negative images in MDD and PTSD patients compared to HCs. Right IFG activation was negatively correlated with the severity of anxiety and depressive symptomatology. In addition, increased seed-to-voxel connectivity of the right IFG as well as increased voxel-to-voxel connectivity was observed in PTSD patients compared to HCs and MDD patients. Conclusions FMRI results therefore suggested a common deficit of depression and anxiety symptomatology reflected by reduced activation in right IFG during cognitive reappraisal as well as diagnosis specific effects in patients with PTSD based on seed-to-voxel and voxel-to-voxel connectivity showing an overactive and hyperconnected salience network. Findings highlight the role of transdiagnostic research to identify disorder specific brain patterns as well as patterns common across disorders.
Traumatic high flow arterioportal fistula. Correction by covered stent. Torres Cuevas BL, Castillo Lara GE, Páez Suárez D, Eilers M. Rev Esp Enferm Dig. 2022 Mar 8. https://doi.org/10.17235/reed.2022.8724/2022. Online ahead of print.
The arterio-portal fistula is a rare entity, generally associated with different causes, among which penetrating trauma stands out. They can occur at the beginning asymptomatic or manifest by a wide spectrum of signs and symptoms with severe limitation of the patient’s quality of life and even compromise it. Immediate therapeutic action, whether surgical or endovascular, is vital for the definitive solution of the primary triggering cause. We present the case of a patient with a stab wound to the abdomen who developed an arterioportal fistula with associated portal hypertension as a complication. It is treated by placing a covered stent at the level of the anomalous communication, with definitive clinical and imaging resolution.
