Dual-pore protocells with multitasking capacities for simultaneous delivery of therapeutic enzymes and drugs in macrophage depletion therapy.

Macrophages are usually present in solid tumors where they participate in tumor progression, angiogenesis, immunosuppression and metastasis. The design of nanocarriers capable of delivering therapeutic agents to specific cell populations has received considerable attention in the last decades. However, the capacity of many of these nanosystems to deliver multiple therapeutic agents with very different chemical properties is more limited. Herein, a novel multitasking nanoplatform capable of delivering large macromolecules and cytotoxic drugs to macrophages is presented. This novel nanosystem has exhibited excellent skills in performing simultaneous tasks, macrophage depletion and glucose starvation, maintaining the oxygen levels in the tissue. This nanodevice is composed of a dual-pore mesoporous silica core with the capacity to house small cytotoxic drugs, such as doxorubicin or zoledronic acid, and large macromolecules, such as glucose oxidase. The external surface of the silica core was coated with a lipid bilayer to avoid the premature release of the housed drugs. Finally, polymeric nanocapsules loaded with catalase were covalently anchored on the outer lipid bilayer, and carboxy-mannose was attached to the exposed side of the nanocapsules to provide selectivity to the macrophages. These nanoassemblies were able to transport enzymes (Gox and CAT), maintaining their catalytic activity. Therefore, they could induce glucose starvation, keeping the oxygen levels in the tissue, owing to the tandem enzymatic reaction. The capacity of these nanoassemblies to deliver therapeutic agents to macrophages was evaluated both in static and under flow conditions, showing a rapid capture of the nanoparticles by the macrophages. Once there, the nanoassemblies also exhibited excellent capacity to induce potent macrophage depletion. This strategy can be directly adapted for the treatment of different malignancies due to the modular nature of the nanoplatform, which can be loaded with different therapeutic agent combinations and pave the way for the development of personalized nanomedicines for diverse types of tumors.

First-Row Transition 7-Oxo-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine Metal Complexes: Antiparasitic Activity and Release Studies.

Leishmaniasis and Chagas disease are still considered neglected illnesses due to the lack of investment in research, despite the fact that almost one million new cases are reported every year. Four 7-oxo-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine (HftpO) first-row transition complexes (Cu, Co, Ni, Zn) have been studied for the first time in vitro against five different species of Leishmania spp. (L. infantum, L. braziliensis, L. donovani, L. peruviana and L. mexicana) as well as Trypanosoma cruzi, showing higher efficacy than the reference commercial drugs. UV and luminescence properties were also evaluated. As a proof of concept, anchoring of a model high-effective-metal complex as an antiparasitic agent on silica nanoparticles was carried out for the first time, and drug-release behaviour was evaluated, assessing this new approach for drug vehiculation.

Position Statement on the Use of Myocardial Strain in Cardiology Routines by the Brazilian Society of Cardiology's Department Of Cardiovascular Imaging - 2023. / Posicionamento do Departamento de Imagem Cardiovascular da Sociedade Brasileira de Cardiologia sobre o Uso do Strain Miocárdico na Rotina do Cardiologista ­ 2023.

Central Illustration : Position Statement on the Use of Myocardial Strain in Cardiology Routines by the Brazilian Society of Cardiology's Department Of Cardiovascular Imaging - 2023 Proposal for including strain in the integrated diastolic function assessment algorithm, adapted from Nagueh et al.67 Am: mitral A-wave duration; Ap: reverse pulmonary A-wave duration; DD: diastolic dysfunction; LA: left atrium; LASr: LA strain reserve; LVGLS: left ventricular global longitudinal strain; TI: tricuspid insufficiency. Confirm concentric remodeling with LVGLS. In LVEF, mitral E wave deceleration time < 160 ms and pulmonary S-wave < D-wave are also parameters of increased filling pressure. This algorithm does not apply to patients with atrial fibrillation (AF), mitral annulus calcification, > mild mitral valve disease, left bundle branch block, paced rhythm, prosthetic valves, or severe primary pulmonary hypertension.

Figura Central : Posicionamento do Departamento de Imagem Cardiovascular da Sociedade Brasileira de Cardiologia sobre o Uso do Strain Miocárdico na Rotina do Cardiologista ­ 2023 Proposta de inclusão do strain no algoritmo integrado de avaliação da função diastólica, adaptado e traduzido de Nagueh et al. 67 AE: átrio esquerdo; Ap: duração da onda A reversa pulmonar; Am: duração da onda A mitral; DD: disfunção diastólica; FEVEr: fração de ejeção do ventrículo esquerdo reduzida; IT: insuficiência tricúspide; SAEr: strain do AE de reservatório; SLGVE: strain longitudinal global do ventrículo esquerdo. Se remodelamento concêntrico, confirmar com SLGVE. Na presença de FEVEr, tempo de desaceleração da onda E mitral (TDE) < 160 ms e onda S < D pulmonar também são parâmetros de pressão de enchimento aumentada. Esse algoritmo não se aplica a pacientes com fibrilação atrial (FA), calcificação do anel mitral ou valvopatia mitral maior que discreta, bloqueio de ramo esquerdo (BRE), ritmo de marca-passo, próteses valvares ou hipertensão pulmonar (HP) primária grave.

Myocarditis as the Initial Presentation of a Refractory Adult-Onset Still's Disease.

We present a case of adult-onset Still's disease, a rare disease that presented with a rare complication, myocarditis. After initial therapy with prednisolone 1 mg/kg/day, the patient experienced dyspnea due to severe pleural effusion and palpitations on account of new-onset supraventricular tachycardia. Therapy with three consecutive pulses of 1000 mg of methylprednisolone and anakinra 100 mg/day proved to be effective, with a progressive resolution of all symptoms. However, at three months follow-up, oligoarthritis recurred along with high serum ferritin. Secondary failure to anakinra was assumed, and a switch to tocilizumab 162 mg was made. Nevertheless, arthralgia of the wrists and knees as well as high serum ferritin still persisted after two months of therapy. Chronic disease was assumed, and the patient switched to canakinumab 4 mg/kg/dose q4week, and a complete resolution of symptoms occurred with normalization of inflammation markers. Follow-up cardiac magnetic resonance showed a complete resolution of heart involvement.

An enzyme-controlled mesoporous nanomachine for triple-responsive delivery.

The construction of a novel enzyme-controlled nanomachine with multiple release mechanisms for on-command delivery is described. This nanodevice was assembled by modifying mesoporous silica nanoparticles with 2-(benzo[d]thiazol-2-yl)phenyl 4-aminobenzoate moieties, and further capped with ß-cyclodextrin-modified glucose oxidase neoglycoenzyme. The device released the encapsulated payload in the presence of H2O2 and acidic media. The use of glucose as an input chemical signal also triggered cargo release through the enzymatic production of gluconic acid and hydrogen peroxide, and the subsequent disruption of the gating mechanism at the mesoporous surface. The nanodevice was successfully employed for the enzyme-controlled release of doxorubicin in HeLa cancer cells.

Sucrose-Responsive Intercommunicated Janus Nanoparticles Network.

Inspired by biological systems, the development of artificial nanoscale materials that communicate over a short distance is still at its early stages. This work shows a new example of a cooperating system with intercommunicated devices at the nanoscale. The system is based on the new sucrose-responsive Janus gold-mesoporous silica (Janus Au-MS) nanoparticles network with two enzyme-powered nanodevices. These nanodevices involve two enzymatic processes based on invertase and glucose oxidase, which are anchored on the Au surfaces of different Janus Au-MS nanoparticles, and N-acetyl-L-cysteine and [Ru(bpy)3]2+ loaded as chemical messengers, respectively. Sucrose acts as the INPUT, triggering the sequential delivery of two different cargoes through the enzymatic control. Nanoscale communication using abiotic nanodevices is a developing potential research field and may prompt several applications in different disciplines, such as nanomedicine.

Direct tissue-sensing reprograms TLR4+ Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients.

CD4+ T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4+ T cells pathogenic functions. Here, we identified a TLR4+ follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. TLR4+ T cells possess a two-pronged pathogenic activity whereby direct TLR4+ engagement by endogenous ligands in the arthritic joint reprograms them from an IL-21 response, known to sponsor antibody production towards an IL-17 inflammatory program recognized to fuel tissue damage. Ex vivo, synovial fluid TLR4+ T cells produced IL-17, but not IL-21. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Mechanistically, we unveiled that T-cell HLA-DR regulates their TLR4 expression. TLR4+ T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program.

Intravenous immunoglobulin as a therapeutic option for patients with worsening COVID-19 under rituximab.

Severe cases of the new COVID-19 are being reported in immunosuppressed patients. The risk seems to depend on the type of immunosuppressive agents used and it is particularly important in patients under the long-lasting effect of rituximab. Information regarding the best therapeutic approach to these patients is scarce and further studies are needed. We present a case of a young woman with rheumatoid arthritis treated with rituximab (last administration 4 months before her admission). She presented with a deteriorating and prolonged SARS-CoV-2 infection, with persistent fever, significant elevation of inflammatory markers and radiological progression. Glucocorticoids and antibiotic therapy were initiated, with no response. Intravenous immunoglobulin was then used with a rapid and exuberant response, anticipating a promising role of this therapy in immunosuppressed patients with COVID-19 under the effect of rituximab.

Ultrasonography Reliability in the Detection of Inflammatory and Structural Abnormalities: An Exercise in Multiple Joints.

BACKGROUND: Ultrasonography is an image technique that allows rheumatologists to visualize structural and inflammatory changes within a joint. The objective of this study was to assess the interobserver and intraobserver reliability of musculoskeletal ultrasound (US) in the detection of inflammatory and destructive joint changes in patients with polyarthritis. METHODS: A Delphi exercise was undertaken to standardize and adapt the EULAR-OMERACT elementary US definitions of inflammatory lesions (effusion, synovial hypertrophy, power Doppler, bone erosions, and synovitis) for each joint. Fifteen patients were analyzed, and video clips of 600 joints were collected. Each joint was scored for the presence of each elementary component, on 2 separate occasions, by 6 examiners. Interobserver and intraobserver agreement analysis was assessed through Fleiss κ coefficient (κ). RESULTS: Considering all patients and all joints, the interobserver values were highest for erosions and lowest for effusion (κ = 0.7314 and κ = 0.6044, respectively). When analyzing different regions, the highest interobserver agreement was for tibiotalar joint (κ = 0.8043) and the lowest for wrist (κ = 0.6767). Intraobserver reliability was excellent for each and all elementary components and anatomical region. CONCLUSIONS: The present study showed either a good or excellent US interobserver and intraobserver reliability in elementary elements and anatomical region. This kind of US reliability exercises are important for standardization of exploration in everyday practice by reducing the variability associated with this imaging technique, and ensuring a greater degree of homogeneity and future comparability in the assessment of disease activity in polyarthritis patients.

Musculoskeletal ultrasound among rheumatologists in Portugal: state of practice and training.

Over the last years, musculoskeletal ultrasound (MSUS) has been increasingly integrated by rheumatologists into clinical practice. Nowadays, it is considered an important imaging modality for the diagnosis, monitoring, and prognosis of various rheumatic diseases, along with its role in the guidance of interventional procedures. Formal training is needed to ensure a skilled and safe MSUS practice. Data regarding the use of MSUS by Portuguese rheumatologists is, however, lacking. Herein, we present a study on the current state of practice and training of MSUS in Portugal.

Janus nanocarrier powered by bi-enzymatic cascade system for smart delivery.

We report herein the assembly of an integrated nanodevice with bi-enzymatic cascade control for on-command cargo release. This nanocarrier is based on Au-mesoporous silica Janus nanoparticles capped at the mesoporous face with benzimidazole/ß-cyclodextrin-glucose oxidase pH-sensitive gate-like ensembles and functionalized with invertase on the gold face. The rationale for this delivery mechanism is based on the invertase-mediated hydrolysis of sucrose yielding glucose, which is further transformed into gluconic acid by glucose oxidase causing the disruption of the pH-sensitive supramolecular gates at the Janus nanoparticles. This enzyme-powered device was successfully employed in the autonomous and on-demand delivery of doxorubicin in HeLa cancer cells.

Portuguese recommendations for the use of ultrasound in rheumatology.

INTRODUCTION: Ultrasound (US) is a relatively cheap, easily available and reliable method to improve the care of rheumatic patients. However, its use in rheumatology practice is very heterogeneous and needs to be standardized. OBJECTIVES: To develop recommendations for the use of US in rheumatic diseases endorsed by the Portuguese Society of Rheumatology. METHODS: A systematic literature review of the available recommendations on the use of ultrasound in rheumatic diseases was performed and presented in a Portuguese Society of Rheumatology meeting to a subgroup of rheumatologists and rheumatology trainees with special interest in the subject. The most important topics to be addressed were selected and assigned to subgroups for literature review and draft recommendations. Following an iterative process of consensus, the final recommendations were developed, and their level of agreement voted anonymously online. A recommendation was approved when the average level of agreement was ≥ 7.5 in a 10-point Likert scale. RESULTS: Fourteen recommendations were produced regarding nine rheumatology topics: rheumatoid arthritis, spondyloarthritis, connective tissue diseases, polymyalgia rheumatica, vasculitis, crystal-deposition diseases, soft tissue rheumatism, osteoarthritis and ultrasound-guided procedures. CONCLUSION: We developed an up-to-date guidance in the form of recommendations for the use of US in nine different areas of rheumatology. As ultrasound is an important imaging modality with increasing use in the rheumatology setting, and there are frequent technological advances in the ultrasound machines and probes, in parallel with continuous associated research, these recommendations should be regularly updated.

Peritenon Extensor Tendon Inflammation in Psoriatic Arthritis Is an Enthesitis-related Lesion.

OBJECTIVE: To analyze the association between enthesitis, synovitis, and peritenon extensor tendon inflammation (PTI) in psoriatic arthritis (PsA). METHODS: PsA patients with swelling of metacarpophalangeal joints were included. Greyscale and power Doppler (PD) were used for synovitis and PTI ultrasound identification. Madrid Sonographic Enthesis Index (MASEI) was used for enthesitis assessment. PD activity was evaluated using PD item of MASEI and PD Outcome Measures in Rheumatology (OMERACT) definition. RESULTS: Synovitis had no association with enthesitis. PTI was associated with PD MASEI and PD OMERACT. Only PD OMERACT showed a positive correlation with PTI. CONCLUSION: In PsA, PTI is associated to enthesitis, as opposed to synovitis.

Glucose-Responsive Enzyme-Controlled Mesoporous Nanomachine with a Layer-by-Layer Supramolecular Architecture.

Here we describe the construction of an integrated and pH-sensitive nanomachine with layer-by-layer supramolecular design and enzymatic control for on-command delivery. The nanodevice comprises a first layer of ß-cyclodextrin-coated gold nanoparticles as capping element of benzimidazole functionalized mesoporous silica nanoparticles, and a second control layer based on an adatamantane-modified glucose oxidase derivative. The nanomachine was selectively fuelled by glucose and successfully employed for the autonomous release of doxorubicin in HeLa cancer cells.

[Ozone Therapy in Knee Osteoarthritis: A Systematic Review]. / Ozonoterapia na Osteoartrose do Joelho: Revisão Sistemática.

INTRODUCTION: The aim of this study was to conduct a systematic review in order to examine the effectiveness of ozone therapy on knee osteoarthritis. The objectives were to evaluate the effect over time of ozone therapy in terms of knee pain, functional improvement and radiographic progression. MATERIAL AND METHODS: A search was carried out on PubMed, Embase, Cochrane Library, Scopus and Web of Science databases to identify randomized and controlled studies focusing on this association. The following descriptors were used in English: ozone therapy, knee osteoarthritis. A descriptive summary and quality assessment was made of all studies included for analysis. RESULTS: Six randomized and controlled studies were identified. The risk of bias assessment demonstrated that one study was considered as having a moderate risk of bias and the remainder a high risk of bias. No quantitative analysis of the data was performed, as the studies included were not sufficiently homogeneous. The participants in the studies were generally elderly patients with mild to moderate knee osteoarthritis. DISCUSSION: The variability of ozone therapy and the comparators demonstrates that there is no standardized therapy. Few studies reported adverse effects, and where they occurred, they were mild and associated with the procedure. CONCLUSION: Ozone therapy proved effective in the short-term in relation to placebo and when combined with hyaluronic acid, but it was not superior to other current treatments. More randomised and controlled studies are needed to evaluate the risks/benefits of ozone therapy, both in the short term and the medium/long term.

Introdução: O presente estudo teve por objetivo realizar uma revisão sistemática de forma a analisar a eficácia da ozonoterapia na osteoartrose do joelho. Os objetivos visaram avaliar o efeito temporal da ozonoterapia na dor no joelho, na melhoria funcional e na progressão radiográfica.Material e Métodos: Realizou-se uma pesquisa nas bases de dados PubMed, Embase, Cochrane Library, Scopus e Web of Science a fim de identificar estudos aleatorizados e controlados que tratassem dessa associação. Utilizaram-se os seguintes descritores em língua inglesa: 'ozone therapy', 'knee osteoarthritis'. Realizou-se um resumo descritivo e avaliação de qualidade de todos os estudos incluídos para análise.Resultados: Identificaram-se seis estudos aleatorizados e controlados relacionados com o objetivo deste trabalho. A avaliação do risco de viés mostrou que um estudo foi considerado como risco moderado de viés e os restantes como risco alto de viés. Não se realizou a análise quantitativa dos dados pois os estudos incluídos não foram suficientemente homogéneos. Os participantes dos estudos eram em geral doentes idosos com osteoartrose do joelho leve a moderada.Discussão: A variabilidade nas intervenções de ozonoterapia e comparadores, demonstra que não existe uma terapêutica estandardizada. Foram poucos os estudos que relataram os efeitos adversos, e quando aconteceu, estes eram ligeiros e associados ao procedimento.Conclusão: A ozonoterapia mostrou eficácia a curto prazo, em relação ao placebo e quando combinada com ácido hialurónico, sem ser promissora em relação aos restantes tratamentos vigentes. É importante que novos estudos aleatorizados e controlados avaliem os benefícios/riscos da ozonoterapia tanto a curto como a médio/longo prazo.

Ligadura dos ramos da artéria torácica interna anastomosada na coronária descendente anterior e efeito nas velocidades do fluxo e no estado funcional do enxerto / Ligation of the branches of the anastomosed internal thoracic artery in the anterior descending coronary artery and the effect on flow velocities and functional status of the graft

Fundamento: Ocorre modificação no fluxo da artéria torácica interna, após sua anastomose na artéria coronária descendente anterior. Objetivo: Avaliar o efeito da ligadura dos ramos proximais da artéria torácica interna anastomosada na artéria coronária descendente anterior, quanto às velocidades e à reserva de velocidade de fluxo coronariano, em pacientes com fração de ejeção do ventrículo esquerdo preservada (> 50%). Métodos: Estudo prospectivo de pacientes com fração de ejeção do ventrículo esquerdo > 50% revascularizados. O Grupo I foi formado por 25 pacientes com ligadura dos grandes ramos da artéria torácica interna antes de sua anastomose na artéria coronária descendente anterior, e o Grupo II por 28 pacientes sem ligadura. Registrou-se o Doppler em nível proximal da artéria torácica interna no pré-operatório, pós-operatório precoce e no pós-operatório tardio de 6 meses. Foram mensurados os picos de velocidade sistólica e diastólica, e as velocidades médias sistólica e diastólica. A reserva de velocidade de fluxo coronariano foi obtida durante o ecocardiograma sob estresse com dobutamina no pós-operatório tardio de 6 meses. Resultados: No pós-operatório precoce, o pico de velocidade sistólica e a velocidade média sistólica diminuíram, enquanto aumentaram o pico de velocidade diastólica e a velocidade média diastólica nos dois grupos (p < 0,05). Do pós-operatório precoce para o tardio em 6 meses, apenas o pico de velocidade diastólica se modificou, diminuindo nos dois grupos (p < 0,05). Durante o ecocardiograma sob estresse com dobutamina, o pico de velocidade diastólica e a velocidade média diastólica aumentaram (p < 0,05), e os grupos não diferiram, mas o pico de velocidade sistólica e a velocidade média sistólica aumentaram apenas no Grupo II (p < 0,05). A reserva de velocidade de fluxo coronariano dos grupos calculada pelo pico de velocidade diastólica (Grupo I = 2,17 ± 0,64 e Grupo II = 2,28 ± 0,63) e pela velocidade média diastólica (Grupo I = 2,27 ± 0,54 e Grupo II = 2,5 ± 0,79) não diferiu. Conclusão: Em pacientes com fração de ejeção do ventrículo esquerdo preservada, a ligadura dos grandes ramos da artéria torácica interna anastomosada na artéria coronária descendente anterior não compromete a reserva de velocidade de fluxo coronariano, mas determina limitação no aumento das velocidades sistólicas

Introduction: Modification of internal thoracic artery flow occurs after its anastomosis in the left anterior descending coronary artery. Objective: To evaluate the effect of ligation of the proximal branches of anastomosed internal thoracic artery flow on the left anterior descending in relation to velocities and coronary flow velocity reserve in patients with left ventricular ejection fraction preserved (> 50%). Methods: Prospective study of patients with left ventricular ejection fraction > 50% and revascularized. Group I was composed of 25 patients with ligation of the major branches of the internal thoracic artery flow before its anastomosis in the left anterior descending coronary artery, and Group II was composed of 28 patients without ligation. Doppler was recorded at the proximal level of internal thoracic artery flow in the preoperative, early postoperative and 6 months later. The systolic peak velocity and diastolic, and systolic mean velocity and diastolic were measured. Coronary flow velocity reserve was obtained during dobutamine stress echocardiography in postoperative period 6 months later. Results: In the postoperative, the systolic peak velocity and the systolic mean velocity decreased while increasing the diastolic peak velocity and the diastolic mean velocity in the groups (p < 0.05). From the postoperative to the postoperative period 6 months later, only the diastolic peak velocity modified, occurring its decrease in the groups (p < 0.05). During the dobutamine stress echocardiography, diastolic peak velocity and the diastolic mean velocity increased (p < 0.05) and groups did not differ, however, the systolic peak velocity and the systolic mean velocity increased only in Group II (p < 0.05). The coronary flow velocity reserve of the groups calculated by diastolic peak velocity (Group I = 2.17 ± 0.64 and Group II =2.28 ± 0.63) and diastolic mean velocity (Group I = 2.27 ± 0.54 and Group II = 2.5 ± 0.79) did not differ. Conclusion: In patients with preserved left ventricular ejection fraction, the ligation of the large branches of the anastomosed internal thoracic artery flow into the left anterior descending coronary artery does not compromise the coronary flow velocity reserve, but determines limitation in the increase of the systolic velocities