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1.
Nat Nanotechnol ; 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501378

RESUMO

Electrochemically converting nitrate ions, a widely distributed nitrogen source in industrial wastewater and polluted groundwater, into ammonia represents a sustainable route for both wastewater treatment and ammonia generation. However, it is currently hindered by low catalytic activities, especially under low nitrate concentrations. Here we report a high-performance Ru-dispersed Cu nanowire catalyst that delivers an industrial-relevant nitrate reduction current of 1 A cm-2 while maintaining a high NH3 Faradaic efficiency of 93%. More importantly, this high nitrate-reduction catalytic activity enables over a 99% nitrate conversion into ammonia, from an industrial wastewater level of 2,000 ppm to a drinkable water level <50 ppm, while still maintaining an over 90% Faradaic efficiency. Coupling the nitrate reduction effluent stream with an air stripping process, we successfully obtained high purity solid NH4Cl and liquid NH3 solution products, which suggests a practical approach to convert wastewater nitrate into valuable ammonia products. Density functional theory calculations reveal that the highly dispersed Ru atoms provide active nitrate reduction sites and the surrounding Cu sites can suppress the main side reaction, the hydrogen evolution reaction.

2.
Cell ; 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35561685

RESUMO

Across biological scales, gene-regulatory networks employ autorepression (negative feedback) to maintain homeostasis and minimize failure from aberrant expression. Here, we present a proof of concept that disrupting transcriptional negative feedback dysregulates viral gene expression to therapeutically inhibit replication and confers a high evolutionary barrier to resistance. We find that nucleic-acid decoys mimicking cis-regulatory sites act as "feedback disruptors," break homeostasis, and increase viral transcription factors to cytotoxic levels (termed "open-loop lethality"). Feedback disruptors against herpesviruses reduced viral replication >2-logs without activating innate immunity, showed sub-nM IC50, synergized with standard-of-care antivirals, and inhibited virus replication in mice. In contrast to approved antivirals where resistance rapidly emerged, no feedback-disruptor escape mutants evolved in long-term cultures. For SARS-CoV-2, disruption of a putative feedback circuit also generated open-loop lethality, reducing viral titers by >1-log. These results demonstrate that generating open-loop lethality, via negative-feedback disruption, may yield a class of antimicrobials with a high genetic barrier to resistance.

3.
Toxicology ; 471: 153161, 2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35364223

RESUMO

This study evaluates safety of FINLAY-FR-02, a vaccine candidate against SARS-CoV-2 based on the recombinant receptor binding domain conjugated to tetanus toxoid, in a preclinical, repeat-dose toxicity and local tolerance study. Sprague Dawley rats were randomly allocated to three experimental groups: control (receiving physiological saline solution); placebo (receiving all vaccine components except antigens) and vaccine group (receiving three doses of the vaccine candidate, 37.5 µg of RBD) administered intramuscularly in hind limbs at 24 h intervals during three days. We evaluated physiological condition, pain, food and water consumption, body temperature, dermal irritability, injection site temperature and inflammation, immunological response, blood chemistry, relative organ weight, histopathology and immunotoxicology. The product was well tolerated; no clinically relevant changes, pain, local effects or adverse systemic toxicological changes or deaths were observed. These preliminary results permitted the Cuban regulatory authorities to authorize clinical trials in humans.

4.
RSC Chem Biol ; 3(2): 242-249, 2022 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-35360883

RESUMO

SARS-CoV-2 infection is mediated by the interaction of the spike glycoprotein trimer via its receptor-binding domain (RBD) with the host's cellular receptor. Vaccines seek to block this interaction by eliciting neutralizing antibodies, most of which are directed toward the RBD. Many protein subunit vaccines require powerful adjuvants to generate a potent antibody response. Here, we report on the use of a SARS-CoV-2 dimeric recombinant RBD combined with Neisseria meningitidis outer membrane vesicles (OMVs), adsorbed on alum, as a promising COVID-19 vaccine candidate. This formulation induces a potent and neutralizing immune response in laboratory animals, which is higher than that of the dimeric RBD alone adsorbed on alum. Sera of people vaccinated with this vaccine candidate, named Soberana01, show a high inhibition level of the RBD-ACE2 interaction using RBD mutants corresponding to SARS-CoV-2 variants of concern and wild-type expressed using the phage display technology. To our knowledge, this is the first time that the immunostimulation effect of N. meningitidis OMVs is evaluated in vaccine candidates against SARS-CoV-2.

5.
BJPsych Open ; 8(3): e86, 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35438069

RESUMO

BACKGROUND: Perfectionism, low self-esteem and external locus of control are psychological constructs linked to insomnia, anxiety and depression. Examining how these constructs impact mental health and serve as risk factors for the development of clinically significant symptoms may help direct psychological support resources and preventative measures for university students. AIMS: To longitudinally examine associations between the aforementioned psychological constructs and symptoms of insomnia, anxiety and depression in a large representative sample of first-year university students. METHOD: Electronic surveys including validated measures of the predictors and outcomes were emailed to all first-year undergraduate students at entry to a major Canadian university, and followed up on at conclusion of the academic year. RESULTS: Compared with healthy sleepers, students screening positive for insomnia had lower self-esteem, higher self-evaluative perfectionism and increased external locus of control (all P < 0.001). Self-evaluative perfectionism (standardised ß = 0.13, P < 0.01), self-esteem (ß = -0.30, P < 0.001) and external locus of control (ß = 0.07, P = 0.02) measured at entry were significantly associated with insomnia symptoms at follow-up. Insomnia symptoms at entry were strong predictors of symptoms of depression (ß = 0.15, P < 0.001) and anxiety (ß = 0.16, P < 0.001) at follow-up, even after controlling for baseline symptoms of those disorders. CONCLUSIONS: Perfectionism, low self-esteem and external locus of control may predispose the development of insomnia symptoms in university students. In turn, insomnia symptoms appear to be robust predictors for depressive and anxiety symptoms. Sleep may be an important prevention target in university students.

6.
Can J Psychiatry ; : 7067437221094549, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35450455

RESUMO

OBJECTIVE: To examine the impact of the COVID-19 pandemic on first year undergraduate student mental health. METHODS: As part of the Queen's University U-Flourish Student Well-Being and Academic Success study, three successive cohorts of students entering undergraduate studies in 2018 (pre-pandemic), 2019 (transitional), and 2020 (during pandemic) completed electronic surveys at entry and completion of first year. Validated self-report measures were used to assess mental health status including symptom levels of anxiety, depression, and insomnia, self-harm and frequency of substance use. Propensity matching and multivariable log-binomial regression were used in comparisons of mental health indicators across the cohorts. RESULTS: Clinically significant symptoms of depression, anxiety, insomnia, and self-harm were reported more frequently in the 2020-2021 cohort, coincident with remote learning and pandemic restrictions. In female students, screen positive rates for anxiety and depression, and suicidal ideation increased from about one-third to just under one-half in association with the pandemic (χ2, p < .01), while increases in mental health concerns were less pronounced among males. Among females, increases in clinically significant symptoms over first year appeared greatest during the pandemic year, while striking decreases in alcohol consumption in both females and males were reported in that same year. Studying under pandemic conditions had a negative impact on student well-being, social relationships and school connectedness, quality of learning experience, leisure activities, and optimism about future prospects. CONCLUSIONS: Mental health concerns including anxiety, depression and sleep problems increased in first year students during the pandemic, especially among females, while alcohol use declined. These findings highlight the negative mental health impact associated with studying under pandemic restrictions involving remote learning and social distancing.

7.
Curr Drug Targets ; 2022 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-35297344

RESUMO

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.

8.
J Pharm Biomed Anal ; 214: 114721, 2022 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-35338945

RESUMO

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.


Assuntos
Glicoconjugados , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Polissacarídeos , Polissacarídeos Bacterianos/química , Vacinas Conjugadas/química
9.
Comput Chem Eng ; 1602022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35342207

RESUMO

Excessive gestational weight gain is a significant public health concern that has been the recent focus of control systems-based interventions. Healthy Mom Zone (HMZ) is an intervention study that aims to develop and validate an individually-tailored and "intensively adaptive" intervention to manage weight gain for pregnant women with overweight or obesity using control engineering approaches. This paper presents how Hybrid Model Predictive Control (HMPC) can be used to assign intervention dosages and consequently generate a prescribed intervention with dosages unique to each individuals needs. A Mixed Logical Dynamical (MLD) model enforces the requirements for categorical (discrete-level) doses of intervention components and their sequential assignment into mixed-integer linear constraints. A comprehensive system model that integrates energy balance and behavior change theory, using data from one HMZ participant, is used to illustrate the workings of the HMPC-based control system for the HMZ intervention. Simulations demonstrate the utility of HMPC as a means for enabling optimized complex interventions in behavioral medicine, and the benefits of a HMPC framework in contrast to conventional interventions relying on "IF-THEN" decision rules.

10.
Artigo em Inglês | MEDLINE | ID: mdl-35206455

RESUMO

Background: Recent advances in mobile and wearable technologies have led to new forms of interventions, called "Just-in-Time Adaptive Interventions" (JITAI). JITAIs interact with the individual at the most appropriate time and provide the most appropriate support depending on the continuously acquired Intensive Longitudinal Data (ILD) on participant physiology, behavior, and contexts. These advances raise an important question: How do we model these data to better understand and intervene on health behaviors? The HeartSteps II study, described here, is a Micro-Randomized Trial (MRT) intended to advance both intervention development and theory-building enabled by the new generation of mobile and wearable technology. Methods: The study involves a year-long deployment of HeartSteps, a JITAI for physical activity and sedentary behavior, with 96 sedentary, overweight, but otherwise healthy adults. The central purpose is twofold: (1) to support the development of modeling approaches for operationalizing dynamic, mathematically rigorous theories of health behavior; and (2) to serve as a testbed for the development of learning algorithms that JITAIs can use to individualize intervention provision in real time at multiple timescales. Discussion and Conclusions: We outline an innovative modeling paradigm to model and use ILD in real- or near-time to individually tailor JITIAs.


Assuntos
Comportamento Sedentário , Telemedicina , Adulto , Terapia Comportamental , Exercício Físico , Comportamentos Relacionados com a Saúde , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Telemedicina/métodos
11.
BMJ Open ; 12(1): e050187, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-35074809

RESUMO

OBJECTIVES: To explore the impact of the COVID-19 pandemic on the experiences and mental health of university students. DESIGN: A cross-sectional study consisting of an electronic survey about students' experiences and concerns during the pandemic and the associated impact. In addition to the quantitative analysis, free-text responses were extracted and analysed using a framework technique. SETTING: Queen's University in Canada and the University of Oxford in the UK. PARTICIPANTS: Undergraduate students at Queen's University and first-year undergraduate students at the University of Oxford were invited to complete the COVID-19 supplement survey. This study included data from 3013 Queen's students as the primary focus and 339 Oxford students as a secondary comparison. RESULTS: Females at Queen's reported greater adherence to government recommendations to prevent the spread of COVID-19 (91.3% vs 86.7%, χ2 p<0.01) and were more likely to self-isolate (63.9% vs 57.0%, χ2 p<0.01) than males. A similar trend was seen among Oxford students. Students' concerns were wide ranging including those related to their learning experience, finances and future academic and career prospects. 78.9% of Queen's students and 50.4% of first-year Oxford students reported worries about the long-term impact on their academic and job prospects. A sizeable proportion of students also reported that the pandemic negatively impacted their plans to continue at university (29.4% of Queen's, 14.2% of Oxford) and disrupted activities important to their mental well-being. Key themes identified in the qualitative component included the negative impacts of social isolation, challenging academic changes and disruption to support services and means of coping. CONCLUSIONS: Overall, findings underscore the importance of addressing areas of student concern and the aspects of student life negatively impacted by the pandemic in order to maintain student well-being and support a successful university experience.


Assuntos
COVID-19 , Canadá/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Saúde Mental , Pandemias , SARS-CoV-2 , Estudantes , Reino Unido/epidemiologia , Universidades
12.
Leuk Lymphoma ; 63(3): 672-675, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34668451

RESUMO

Acute promyelocytic leukemia (APL) is characterized by the chromosomal translocation t(15;17) and the resulting gene PML-RARA, used for measurable residual disease (MRD) monitoring. Despite highly effective therapy for APL, MRD monitoring practices are not fully established. We aimed to assess the value of MRD monitoring by RT-qPCR in patients with APL treated with ATRA and arsenic trioxide +/- GO. We reviewed 223 patients with APL treated with this regimen. RT-qPCR for PML-RARA was measured every 3 months, and at 12, 18, and 24 months after therapy. Seven patients relapsed. Time to relapse was 7.9-12.4 months in 6 patients, and one patient relapsed after 79.5 months. These data show that MRD monitoring may be important for the detection of relapse in patients treated with this regimen within one year after completing therapy, however, since late molecular relapse is rare, our data suggest a low value of MRD monitoring beyond that first year.


Assuntos
Arsenicais , Leucemia Promielocítica Aguda , Trióxido de Arsênio/efeitos adversos , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Óxidos , Recidiva , Translocação Genética , Tretinoína
13.
Am J Physiol Renal Physiol ; 322(1): F27-F41, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34806449

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the polycystin 1 (PKD1) or polycystin 2 genes, presents with progressive development of kidney cysts and eventual end-stage kidney disease with limited treatment options. Previous work has shown that metformin reduces cyst growth in rapid ADPKD mouse models via inhibition of cystic fibrosis transmembrane conductance regulator-mediated fluid secretion, mammalian target of rapamycin, and cAMP pathways. The present study importantly tested the effectiveness of metformin as a therapy for ADPKD in a more clinically relevant Pkd1RC/RC mouse model, homozygous for the R3277C knockin point mutation in the Pkd1 gene. This mutation causes ADPKD in humans. Pkd1RC/RC male and female mice, which have a slow progression to end-stage kidney disease, received metformin (300 mg/kg/day in drinking water vs. water alone) from 3 to 9 or 12 mo of age. As previously reported, Pkd1RC/RC females had a more severe disease phenotype as compared with males. Metformin treatment reduced the ratio of total kidney weight-to-body weight relative to age-matched and sex-matched untreated controls at both 9 and 12 mo and reduced the cystic index in females at 9 mo. Metformin also increased glomerular filtration rate, lowered systolic blood pressure, improved anemia, and lowered blood urea nitrogen levels relative to controls in both sexes. Moreover, metformin reduced gene expression of key inflammatory markers and both gene and protein expression of kidney injury marker-1 and cyclin-dependent kinase-1 versus untreated controls. Altogether, these findings suggest several beneficial effects of metformin in this highly relevant slowly progressive ADPKD mouse model, which may help inform new ADPKD therapies in patients.NEW & NOTEWORTHY Metformin treatment improved ADPKD disease severity in a relevant, slowly progressive ADPKD mouse model that recapitulates a PKD-associated PKD1 mutation. Relative to controls, metformin reduced kidney weight/body weight, cystic index and BUN levels, while improving GFR, blood pressure and anemia. Metformin also reduced key inflammatory and injury markers, along with cell proliferation markers. These findings suggest several beneficial effects of metformin in this ADPKD mouse model, which may help inform new ADPKD therapies in patients.


Assuntos
Falência Renal Crônica/prevenção & controle , Rim/efeitos dos fármacos , Metformina/farmacologia , Rim Policístico Autossômico Dominante/tratamento farmacológico , Fármacos Renais/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Predisposição Genética para Doença , Taxa de Filtração Glomerular/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Falência Renal Crônica/metabolismo , Falência Renal Crônica/patologia , Falência Renal Crônica/fisiopatologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Rim Policístico Autossômico Dominante/metabolismo , Rim Policístico Autossômico Dominante/patologia , Rim Policístico Autossômico Dominante/fisiopatologia , Canais de Cátion TRPP/genética , Fatores de Tempo
14.
Methods Mol Biol ; 2371: 143-157, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34596847

RESUMO

Multicomponent reactions (MCRs) are recently expanding the plethora of solid-phase protocols for the synthesis and derivatization of peptides. Herein, we describe a solid-phase-compatible strategy based on MCRs as a powerful strategy for peptide cyclization and ligation . We illustrate, using Gramicidin S as a model peptide, how the execution of on-resin Ugi reactions enables the simultaneous backbone N-functionalization and cyclization, which are important types of derivatizations in peptide-based drug development or for incorporation of conjugation handles, or labels.


Assuntos
Peptídeos Cíclicos/química , Ciclização , Gramicidina
15.
Curr Oncol Rep ; 2022 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-35366167

RESUMO

PURPOSE OF REVIEW: Patients diagnosed with CLL have an increased susceptibility to infections. Over the years, there has been a shift of the treatment arsenal to an increasing use of chemotherapy-free regimens, particularly small molecule inhibitors. These therapies have proven to be effective and have a favorable toxicity profile. Infections continue to represent a significant complication in the era of novel therapies. RECENT FINDINGS: Recent studies continue to bring new insights into the effects of modern therapies on the immune system. Evidence supporting infection prevention strategies is scarce. We will review the available recommendations to prevent infections in patients with CLL treated with novel therapies. New CLL therapies are broadly adopted in routine practice, requiring optimization of their side effects. Timely prevention, recognition, and treatment of infections should remain an important aspect of the standard management of a patient with CLL.

16.
Anal Bioanal Chem ; 413(30): 7559-7585, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34739558

RESUMO

Subunit vaccines based on the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 provide one of the most promising strategies to fight the COVID-19 pandemic. The detailed characterization of the protein primary structure by mass spectrometry (MS) is mandatory, as described in ICHQ6B guidelines. In this work, several recombinant RBD proteins produced in five expression systems were characterized using a non-conventional protocol known as in-solution buffer-free digestion (BFD). In a single ESI-MS spectrum, BFD allowed very high sequence coverage (≥ 99%) and the detection of highly hydrophilic regions, including very short and hydrophilic peptides (2-8 amino acids), and the His6-tagged C-terminal peptide carrying several post-translational modifications at Cys538 such as cysteinylation, homocysteinylation, glutathionylation, truncated glutathionylation, and cyanylation, among others. The analysis using the conventional digestion protocol allowed lower sequence coverage (80-90%) and did not detect peptides carrying most of the above-mentioned PTMs. The two C-terminal peptides of a dimer [RBD(319-541)-(His)6]2 linked by an intermolecular disulfide bond (Cys538-Cys538) with twelve histidine residues were only detected by BFD. This protocol allows the detection of the four disulfide bonds present in the native RBD, low-abundance scrambling variants, free cysteine residues, O-glycoforms, and incomplete processing of the N-terminal end, if present. Artifacts generated by the in-solution BFD protocol were also characterized. BFD can be easily implemented; it has been applied to the characterization of the active pharmaceutical ingredient of two RBD-based vaccines, and we foresee that it can be also helpful to the characterization of mutated RBDs.


Assuntos
Cisteína/metabolismo , Fragmentos de Peptídeos/metabolismo , Processamento de Proteína Pós-Traducional , Espectrometria de Massas por Ionização por Electrospray/métodos , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Cisteína/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Fragmentos de Peptídeos/química , Ligação Proteica , Domínios Proteicos , Subunidades Proteicas
17.
Am Surg ; : 31348211047496, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615400

RESUMO

INTRODUCTION: Computed tomography scans became the mainstay of emergency department (ED) evaluation of trauma patients including those with a high Glasgow Coma Scale (GCS) and a low Injury Severity Score (ISS). We elected to find the value of abdominal and pelvic CT in patients with negative physical examination and Focused Assessment of Sonography for Trauma (FAST) on arrival to the ED. METHODS: This study is a retrospective analysis of 901 consecutive patients from 2017 to 2019 who presented to the ED with level 2 and 3 activation criteria. Each patient received a physical examination, CT abdomen and pelvis, and FAST exam. Data were collected on external factor including GCS, ISS, age, sex, comorbidities, anticoagulation use, and surgical intervention. The patients were divided into 2 groups, Group A and B. Group A consisted of patients with a negative physical exam, FAST, and CT result. Group B included patients with a negative physical exam and FAST exam with positive CT findings. Statistical analysis was done using a Student's t-test and chi-square test for significance value of P < .05. Institutional Review Board approval was obtained for this study. RESULTS: A total of 901 patients were analyzed which included 489 (54.3%) male and 412 (45.7%) female with a mean age of 56.2 (SD = 22.62) years. Out of the 901 patients, 461 patients received a physical, FAST, and CT exam. Group A consisted of 442 (95.9%) patients and Group B had 19 (4.1%) patients. Both groups were similar in GCS and ISS scoring with no significance difference in age, sex, comorbidities, and anticoagulation use. There was a significant difference in the ICU and hospital mean length of stay when CT scan was positive [2 (SD = 4.23) days vs. .6 (SD = 1.33) days with P < .0001 and 4.57 (SD ± 4.17) days vs. 2.5 (SD = 2.00) days with P < .0001, respectively]. The CT findings of the 19 patients in group B consisted of 6 incidentalomas, 5 vertebral compression fractures, 4 pelvic bone fractures, 1 minor liver contusion, 1 non-specific bowel thickening, 1 non-displaced rib fracture, and 1 case of small amount of free fluid in the pelvis. None of the CT findings required surgical intervention. CONCLUSION: Computed tomography of the abdomen and pelvis in trauma patients with high GCS and low ISS with initial negative physical and FAST examination did not provide additional critical information.

18.
Life (Basel) ; 11(10)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34685408

RESUMO

Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite's leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC50 = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC50 = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization.

19.
Mediterr J Hematol Infect Dis ; 13(1): e2021044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276913

RESUMO

Ibrutinib is a well-tolerated and effective therapy used for the treatment of chronic lymphocytic leukemia (CLL). However, its use has been associated with cardiovascular events such as atrial fibrillation (Afib), hypertension, and ventricular arrhythmias. Cardiac arrhythmias represent a significant cause of morbidity and mortality. Implanted loop recorders have been integrated into our clinical practice and have been considered a useful tool in guiding the management of patients with cardiac arrhythmias. We report a case that describes our experience on a patient diagnosed with CLL treated with ibrutinib.

20.
ACS Chem Biol ; 16(7): 1223-1233, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34219448

RESUMO

Controlling the global COVID-19 pandemic depends, among other measures, on developing preventive vaccines at an unprecedented pace. Vaccines approved for use and those in development intend to elicit neutralizing antibodies to block viral sites binding to the host's cellular receptors. Virus infection is mediated by the spike glycoprotein trimer on the virion surface via its receptor binding domain (RBD). Antibody response to this domain is an important outcome of immunization and correlates well with viral neutralization. Here, we show that macromolecular constructs with recombinant RBD conjugated to tetanus toxoid (TT) induce a potent immune response in laboratory animals. Some advantages of immunization with RBD-TT conjugates include a predominant IgG immune response due to affinity maturation and long-term specific B-memory cells. These result demonstrate the potential of the conjugate COVID-19 vaccine candidates and enable their advance to clinical evaluation under the name SOBERANA02, paving the way for other antiviral conjugate vaccines.


Assuntos
Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Toxoide Tetânico/química , Vacinas Conjugadas/administração & dosagem , Animais , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vacinação , Vacinas Conjugadas/imunologia
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