Susceptibility of Leishmania to novel pentavalent organometallics: Investigating impact on DNA and membrane integrity in antimony(III)-sensitive and -resistant strains.

The aim the present study was to investigate the impact of novel pentavalent organobismuth and organoantimony complexes on membrane integrity and their interaction with DNA, activity against Sb(III)-sensitive and -resistant Leishmania strains and toxicity in mammalian peritoneal macrophages. Ph3M(L)2 type complexes were synthesized, where M = Sb(V) or Bi(V) and L = deprotonated 3-(dimethylamino)benzoic acid or 2-acetylbenzoic acid. Both organobismuth(V) and organoantimony(V) complexes exhibited efficacy at micromolar concentrations against Leishmania amazonensis and L. infantum but only the later ones demonstrated biocompatibility. Ph3Sb(L1)2 and Ph3Bi(L1)2 demonstrated distinct susceptibility profiles compared to inorganic Sb(III)-resistant strains of MRPA-overexpressing L. amazonensis and AQP1-mutated L. guyanensis. These complexes were able to permeate the cell membrane and interact with the Leishmania DNA, suggesting that this effect may contribute to the parasite growth inhibition via apoptosis. Taken altogether, our data substantiate the notion of a distinct mechanism of uptake pathway and action in Leishmania for these organometallic complexes, distinguishing them from the conventional inorganic antimonial drugs.

Plasma collection and supply in Europe: Proceedings of an International Plasma and Fractionation Association and European Blood Alliance symposium.

At the symposium organized by the International Plasma and Fractionation Association and European Blood Alliance, experts presented their views and experiences showing that the public sector and its blood establishments may strengthen the collection and increase the supply of plasma using the right strategies in plasma donor recruitment, retention and protection, scaling-up collection by increasing the number of donors within improved/new infrastructure, supportive funding, policies and legislation as well as harmonization of clinical guidelines and the collaboration of all stakeholders. Such approaches should contribute to increased plasma collection in Europe to meet patients' needs for plasma-derived medicinal products, notably immunoglobulins and avoid shortages. Overall, presentations and discussions confirmed that European non-profit transfusion institutions are committed to increasing the collection of plasma for fractionation from unpaid donors through dedicated programmes as well as novel strategies and research.

Ellagic Acid Inhibits Neuroinflammation and Cognitive Impairment Induced by Lipopolysaccharides.

Neuroinflammation is a predisposing factor for the development of cognitive impairment and dementia. Among the new molecules that are currently being studied, ellagic acid (EA) has stood out for its neuroprotective properties. The present study investigated the effects of ellagic acid in the object recognition test, oxidative stress, cholinergic neurotransmission, glial cell expression, and phosphorylated Tau protein expression. For this, 32 male Wistar rats received an intraperitoneal (IP) application of lipopolysaccharides (LPS) at a dose of 250 µg/kg or 0.9% saline solution (SAL) for 8 days. Two hours after the IP injections, the animals received 100 mg/kg of EA or SAL via intragastric gavage. Behavioral parameters (open field test and object recognition) were performed on days 5, 6, and 7 of the experimental periods. The results showed that the treatment with EA in the LPS group was able to inhibit cognitive impairment, modulate the immune system response by significantly reducing glial cell expression, attenuating phosphorylated Tau and oxidative damage with consequent improvement in the antioxidant system, as well as preventing the increase of acetylcholinesterase activity. Thus, the neuroprotective effects of EA and its therapeutic potential in cognitive disorders secondary to neuroinflammation were demonstrated.

New Heteroleptic Ruthenium(II) Complexes with Sulfamethoxypyridazine and Diimines as Potential Antitumor Agents.

Two new complexes of Ru(II) with mixed ligands were prepared: [Ru(bpy)2smp](PF6) (1) and [Ru(phen)2smp](PF6) (2), in which smp = sulfamethoxypyridazine; bpy = 2,2'-bipyridine; phen = 1,10-phenanthroline. The complexes have been characterized by elemental and conductivity analyses; infrared, NMR, and electrospray ionization mass spectroscopies; and X-ray diffraction of single crystal. Structural analyses reveal a distorted octahedral geometry around Ru(II) that is bound to two bpy (in 1) or two phen (in 2) via their two heterocyclic nitrogens and to two nitrogen atoms from sulfamethoxypyridazine-one of the methoxypyridazine ring and the sulfonamidic nitrogen, which is deprotonated. Both complexes inhibit the growth of chronic myelogenous leukemia cells. The interaction of the complexes with bovine serum albumin and DNA is described. DNA footprinting using an oligonucleotide as substrate showed the complexes' preference for thymine base rich sites. It is worth notifying that the complexes interact with the Src homology SH3 domain of the Abl tyrosine kinase protein. Abl protein is involved in signal transduction and implicated in the development of chronic myelogenous leukemia. Nuclear magnetic resonance (NMR) studies of the interaction of complex 2 with the Abl-SH3 domain showed that the most affected residues were T79, G97, W99, and Y115.

1,2,3-triazole-, arylamino- and thio-substituted 1,4-naphthoquinones: potent antitumor activity, electrochemical aspects, and bioisosteric replacement of C-ring-modified lapachones.

1,2,3-Triazole-, arylamino- and thio-substituted naphthoquinones (24, 8, and 2 representatives, respectively) were synthesized in moderate yields and evaluated against several human cancer cell lines (blood, ovarian, breast, central nervous system, colon, and prostate cancers and melanoma), showing, for some of them, IC50 values below 2 µM. The cytotoxic potential of the tested naphthoquinones was also assayed on non-tumor cells such as human peripheral blood mononucluear cells (PBMC) and two murine fibroblast lines (L929 and V79 cells). α-Lapachone- and nor-α-lapachone-based 1,2,3-triazoles and arylamino-substituted naphthoquinones showed potent cytotoxicity against different cancer cell lines. The compounds may represent promising new lead derivatives for anticancer drug development. The electrochemical properties of selected compounds were evaluated in an attempt to correlate them with antitumor activity.

Hyponatremia in the prognosis of acute ischemic stroke.

BACKGROUND: Hyponatremia is a risk factor for stroke and cardiovascular disease. Even mild hyponatremia is associated with increased 30-day mortality after myocardial infarction, and it has recently shown to increase the 3-year mortality after a stroke. In this work, we investigated both acute and chronic clinical outcomes after a stroke in hyponatremic patients. METHODS: We reviewed all patients admitted between 2004 and 2011 with the diagnosis of acute ischemic stroke. Hyponatremia was defined as serum sodium level less than 135 mmol/L and recorded on admission. All hemorrhagic strokes were excluded. Data were analyzed using multivariate logistic regression. RESULTS: A total of 3585 patients with stroke were identified. Hyponatremia was observed in 565 (16%) patients. Baseline characteristics were similar between groups except heart failure (P = .015), cancer (P = .038), diabetes (P < .001), and dementia (P = .015). Hyponatremic patients had higher National Institutes of Health Stroke Scale (NIHSS) score on admission (P = .032) and at discharge (P = .02). Despite similar modified Barthel Index (mBI) preadmission, patients with hyponatremia had worse mBI on admission (P = .049). Hyponatremia was associated with higher mortality in hospital (P = .039) and at 3-month (P = .001) and 12-month follow-ups (P = .001). A poorer discharge disposition was seen in the hyponatremia group (P = .004). Complications during admission were similar between groups except for urinary infection (P = .008). Patients with hyponatremia had worse NIHSS and mBI values on admission, and their deficits worsened during their hospitalization. CONCLUSIONS: This is the first study to demonstrate that hyponatremia is associated with acute mortality and poorer discharge dispositions and to confirm that higher mortality occurs in these patients, even after 12 months after a stroke.

Novel triphenylantimony(V) and triphenylbismuth(V) complexes with benzoic acid derivatives: structural characterization, in vitro antileishmanial and antibacterial activities and cytotoxicity against macrophages.

Two novel organoantimony(V) and two organobismuth(V) complexes of the type ML2 were synthesized, with L = acetylsalicylic acid (HL1) or 3-acetoxybenzoic acid (HL2) and M = triphenylantimony(V) (M1) or triphenylbismuth(V) (M2). Complexes, [M1(L1)2] (1), [M1(L2)2]∙CHCl3 (2), [M2(L1)2], (3) and [M2(L2)2] (4), were characterized by elemental analysis, IR and NMR. Crystal structures of triphenylantimony(V) dicarboxylate complexes 1 and 2 were determined by single crystal X-ray diffraction. Structural analyses revealed that 1 and 2 adopt five-coordinated extremely distorted trigonal bipyramidal geometries, binding with three phenyl groups in the equatorial position and two deprotonated organic ligands (L) in the axial sites. The metal complexes, their metal salts and ligands were evaluated in vitro for their activities against Leishmania infantum and amazonensis promastigotes and Staphylococcus aureus and Pseudomonas aeruginosa bacteria. Both the metal complexes showed antileishmanial and antibacterial activities but the bismuth complexes were the most active. Intriguingly, complexation of organobismuth(V) salt reduced its activity against Leishmania, but increased it against bacteria. In vitro cytotoxic test of these complexes against murine macrophages showed that antimony(V) complexes were the least toxic. Considering the selectivity indexes, organoantimony(V) complexes emerge as the most promising antileishmanial agents and organobismuth(V) complex 3 as the best antibacterial agent.

Social Justice and the Political Organization of Behavior Analysts: Changing the Institutional Practices of a Brazilian Association.

Given the advancement of behavioral research in culture and social behavior, it seems natural for the community of behavior analysts to progress towards increased political engagement and a dedication to social justice. To reach this goal, it is necessary to act inside one's own communities and organizations. The purpose of this article is to report on the efforts of the Brazilian Association for Behavioral Psychology and Medicine (ABPMC) to increase equity and social justice during the 2017-2018 term. First, we present an overview of the ABPMC. Next, we describe the process of identifying, planning, and implementing equity and social justice actions in the association. The problems targeted were the discontinuation of policies from one term to another, elitism and centralization, the lack of topics with social and political relevance in the annual conference's scientific program, and the lack of support for the participation of women (especially mothers) in clinical and academic practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s40617-020-00510-2.

Synthesis and anti-Trypanosoma cruzi activity of naphthoquinone-containing triazoles: electrochemical studies on the effects of the quinoidal moiety.

In our continued search for novel trypanocidal compounds, twenty-six derivatives of para- and ortho-naphthoquinones coupled to 1,2,3-triazoles were synthesized. These compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Compounds 17-24, 28-30 and 36-38 are described herein for the first time. Three of these novel compounds (28-30) were found to be more potent than the standard drug benznidazole, with IC50/24h values between 6.8 and 80.8µM. Analysis of the toxicity to heart muscle cells led to LC50/24h of <125, 63.1 and 281.6µM for 28, 29 and 30, respectively. Displaying a selectivity index of 34.3, compound 30 will be further evaluated in vivo. The electrochemical properties of selected compounds were evaluated in an attempt to find correlations with trypanocidal activity, and it was observed that more electrophilic quinones were generally more potent.

N(4)-tolyl-2-acetylpyridine thiosemicarbazones and their platinum(II,IV) and gold(III) complexes: cytotoxicity against human glioma cells and studies on the mode of action.

Complexes [Au(2Ac4oT)Cl][AuCl2] (1), [Au(Hpy2Ac4mT)Cl2]Cl·H2O (2), [Au(Hpy2Ac4pT)Cl2]Cl (3), [Pt(H2Ac4oT)Cl]Cl (4), [Pt(2Ac4mT)Cl]·H2O (5), [Pt(2Ac4pT)Cl] (6) and [Pt(L)Cl2OH], L = 2Ac4mT (7), 2Ac4oT (8), 2Ac4pT (9) were prepared with N(4)-ortho- (H2Ac4oT), N(4)-meta- (H2Ac4mT) and N(4)-para- (H2Ac4pT) tolyl-2-acetylpyridine thiosemicarbazone. The cytotoxic activities of all compounds were assayed against U-87 and T-98 human malignant glioma cell lines. Upon coordination cytotoxicity improved in 2, 5 and 8. In general, the gold(III) complexes were more cytotoxic than those with platinum(II,IV). Several of these compounds proved to be more active than cisplatin and auranofin used as controls. The gold(III) complexes probably act by inhibiting the activity of thioredoxin reductase enzyme whereas the mode of action of the platinum(II,IV) complexes involves binding to DNA. Cells treated with the studied compounds presented morphological changes such as cell shrinkage and blebs formation, which indicate cell death by apoptosis induction.

(Acetylacetonato-κ2O,O')(2,2'-bipyridine-κ2N,N')iodidocopper(II): a compound with two molecules in the asymmetric unit due to different π-π interactions.

The crystal structure of the title complex, [Cu(C5H7O2)I(C10H8N2)], in the space group P1 with Z = 4, is stabilized by π-π interactions and weak C-H···I interactions. The presence of two molecules in the asymmetric unit is associated with different intermolecular π-π interactions between two symmetry-related molecules of each type.

Influence of exercise order on repetition performance among all possible combinations on resistance training.

The purposes of this study were to compare the repetition performance and rating of perceived exertion (RPE) in different exercises order of three resistance training (RT) exercises: bench press (BP), shoulder press (SP), and triceps extension (TE). Twelve trained men participated in this study (26.75 ± 2.49 years; 177 ± 4.66 cm; 77.7 ± 6.20 kg; 12.61 ± 2.01% body fat; RT experience 3.58 ± 1.24 years). Data were collected in two phases: (1) 10 RM test for BP, SP, and TE and (2) performance of six RT sequences. The sequences were: SEQA (BP, SP, TE), SEQB (BP, TE, SP), SEQC (SP, BP, TE), SEQD (SP, TE, BP), SEQE (TE, BP, SP), and SEQF (TE, SP, BP). The repetition performance on SEQD was significantly smaller than SEQE and SEQF. No significant differences were found for repetition performance and RPE among other sequences. These data indicate that priority might be given to exercises performed in the beginning of the RT session.

Communication disorders in the correctional system: a systematic review.

OBTECTIVES: Good communication is essential for resolving social conflicts, especially in closed communities such as prisons. When communication is interrupted by factors such as hearing loss or difficulties in coordination, voice, language, fluency, or disruption of any of the biological systems required to communicate, Human Communication Disorders can appear. This review aimed to identify the most prevalent communication disorders amongst prison inmates. MATERIAL AND METHOD: Systematic review through databases of studies that analyze individual inmates with communication disorders over the last 38 years. After reading the titles and abstracts and applying the eligibility criteria, 25 articles were selected and included in the final review. RESULTS: A sample of 2,188 individuals was evaluated, two studies were conducted with a female population only, while twelve studied exclusively males, and 11 articles had a mixed population. All the studies included evaluated language and communication disorders in general, with language impairment being more prevalent There are no English language studies evaluating language and communication disorders in incarcerated individuals from African countries, Latin America or Asia. DISCUSSION: Inmates have a high prevalence of language and communication disorders, and thus end up being more vulnerable within the prison system. Speech therapists are important members of the legal workforce and improve the health, well-being and participation of people in contact with or at risk of contact with the judicial system through the prevention, early detection, assessment and treatment of communication disorders.

Experimental charge density and topological analysis of tetraaquabis(hydrogenmaleato)nickel(II): a comparison with Hirshfeld atom refinement.

Experimental charge density analysis is conducted on the coordination compound tetraaquabis(hydrogenmaleato)nickel(II), which exhibits a short intramolecular hydrogen bond. Through topological analysis, the nature of Ni-O bonds is concluded to be intermediate between ionic and covalent, but mainly presenting an ionic character, while the short hydrogen bond is classified as covalent in nature. The compound was also analysed after Hirshfeld atom refinement performed using NoSpherA2. A topological analysis was conducted on the molecular wavefunction and the results are compared with those obtained from experiment. In general, there is good agreement between the refinements, and the chemical bonds involving H atoms are in better agreement with what is expected from neutron data after HAR than they are after multipole refinement.

Prevalence of temporomandibular disorders in the Brazilian population: A systematic review and meta-analysis.

This systematic review aimed to assess the prevalence of temporomandibular disorders (TMD) in the Brazilian population, with studies that used the RDC/TMD or DC/TMD as diagnostic tools. A total of 6365 people from 11 studies were included. Sample mean age ranged from 12 to 69.5 years. The pooled prevalence of TMD was 33.6% (95% CI 31.5-35.8; I2 = 37.2). Prevalence of TMD was higher in females (37.0%) than in males (29.3%). Our results indicate that TMD is a prevalent condition across Brazil's territories. The results from this meta-analysis can help calculate more accurate sample sizes for future studies.

Burden of Disease and Cost of Illness of Inflammatory Bowel Diseases in Portugal.

Background: Inflammatory bowel diseases' (IBD) increasing incidence and prevalence place a heavy health and economic burden on society. Objectives: This study assesses the burden and cost of IBD in Portugal to support the definition of health policies, resource allocation, and patient care. Methods: The burden of disease was expressed using disability-adjusted life years (DALY). Costs were estimated considering the societal perspective, using a prevalence-based model and prices established by law. An expert panel composed of 5 expert Portuguese gastroenterologists and a patient-reported study were conducted to support the cost analysis and fill in information gaps. Results: In Portugal, with a prevalence of 24,069 IBD patients and an incidence of 15/100,000, the burden of disease was estimated at 6,067 DALYs: 507 resulting from premature deaths and 5,560 from disability. Total cost was estimated at EUR 146 million per year, with direct costs representing 59%. Average yearly cost per IBD patient is EUR 6,075, where 60% is related to Crohn's disease and 40% to ulcerative colitis (UC). Conclusion: This study estimates the annual health burden and cost of IBD in Portugal, thus generating information with the intent to raise awareness of the need to advance health policies as well as better clinical and economic decisions in this pathology.

Contexto: A crescente incidência e prevalência das Doenças Inflamatórias Intestinais (DII) representam um pesado fardo para a saúde e economia na sociedade. Objetivos: Este estudo avalia o custo e a carga da DII em Portugal, com o objetivo de suportar a definição de políticas de saúde, alocação de recursos e cuidados com o doente. Métodos: A carga da doença foi calculada utilizando anos de vida ajustados à incapacidade (DALY). Os custos foram estimados tendo em conta a perspetiva da sociedade, utilizando um modelo baseado na prevalência e preços estabelecidos por lei. Foi realizado um painel de peritos, composto por 5 gastroenterologistas portugueses, assim como um estudo de mercado a doentes, de forma a suportar a análise de custos e colmatar lacunas de informação. Resultados: Em Portugal, com uma prevalência de 24,069 doentes e uma incidência de 15/100,000, o peso das DII foi estimado em 6.067 DALYs: 507 dos quais resultantes de mortes prematuras e 5.560 de incapacidade. O custo total foi estimado em 146 milhões de euros por ano, com os custos diretos a representarem 59% do total. O custo médio anual por doente de DII é de 6.075 EUR, onde 60% está relacionado com Doença de Crohn (DC) e 40% com Colite Ulcerosa. Conclusão: Este estudo estima os encargos anuais para a saúde e o custo da DII em Portugal, gerando informação relevante, com o intuito de alertar para a necessidade de uma evolução nas políticas de saúde, assim como como suportar melhores decisões clínicas e económicas nesta patologia.

Antitumor copper(II) complexes with hydroxyanthraquinones and N,N-heterocyclic ligands.

Five ternary copper(II) complexes, [Cu2(phen)2(L1)(ClO4)2] (1), [Cu2(phen)2(L1)(DMSO)2](PF6)2 (2), [Cu2(bpy)2(L1)(ClO4)2(H2O)2] (3), [Cu2(dmp)2(L1)(ClO4)2(H2O)2] (4), and [Cu(phen)(L2)]2(ClO4)2 (5), in which phen = 1,10-phenanthroline, bpy = 2,2'-bipyridine, dmp = 2,9-dimethyl-1,10-phenanthroline, H2L1 = 1,4-dihydroxyanthracene-9,10-dione and HL2 = 1-hydroxyanthracene-9,10-dione, DMSO = dimethylsulfoxide, were synthesized and fully characterized. Complex 2 was obtained through the substitution of perchlorate for DMSO. When two hydroxyquinone groups are present, L1 makes a bridge between two Cu(II) ions, which also bind two nitrogens of the respective diimine ligand. The compounds bind to calf thymus DNA and oxidatively cleave pUC19 DNA according to the following order of activity 1 > 4-5 > 3. Furthermore, complexes 1, 3, 4 and 5 inhibit topoisomerase-I activity and the growth of myelogenous leukemia cells with the IC50 values of 1.13, 10.60, 0.078, and 1.84 µmol L-1, respectively. Complexes 1 and 4 are the most active in cancer cells and in DNA cleavage.

An Adjusted Treatment Comparison Comparing Amivantamab Versus Real-World Clinical Practice in Europe and the United States for Patients with Advanced Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor Exon 20 Insertion Mutations.

INTRODUCTION: Patients with advanced, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (Exon20ins) have poor prognoses, exacerbated by a previous lack of specific treatment guidelines and unmet need for targeted therapies. Amivantamab, an EGFR and MET bispecific antibody, demonstrated efficacy and tolerability in patients with advanced EGFR-mutated NSCLC with Exon20ins following platinum-based therapy in CHRYSALIS (NCT02609776; Cohort D+). Since CHRYSALIS was single-arm, individual patient data (IPD)-based adjusted analyses versus similar patients in real-world clinical practice (RWCP) were conducted to generate comparative evidence. METHODS: RWCP cohorts were derived from seven European and US real-world sources, comprising patients fulfilling CHRYSALIS Cohort D+ eligibility criteria. Amivantamab was compared with a basket of RWCP treatments. Differences in prognostic characteristics were adjusted for using inverse probability weighting (IPW; average treatment effect among the treated [ATT]). Balance between cohorts was assessed using standardized mean differences (SMDs). Overall response rate (ORR; investigator- [INV] and independent review committee-assessed [IRC]), overall survival (OS), progression-free survival (PFS; INV and IRC) and time-to-next treatment (TTNT) were compared. Binary and time-to-event endpoints were analyzed using weighted logistic regression and proportional hazards regression, respectively. RESULTS: Pre-adjustment, baseline characteristics were comparable between cohorts. IPW ATT-adjustment improved comparability, giving closely matched characteristics. ORR (INV) was 36.8% for amivantamab versus 17.0% for the adjusted EU + US cohort (response rate ratio [RR]: 2.16). Median OS, PFS (INV) and TTNT were 22.77 versus 12.52 months (hazard ratio [HR]: 0.47; p < 0.0001), 6.93 versus 4.17 months (HR: 0.55; p < 0.0001) and 12.42 versus 5.36 months (HR: 0.44; p < 0.0001) for amivantamab versus the adjusted EU + US cohort, respectively. Results were consistent versus EU- and US-only cohorts, and when using IRC assessment. CONCLUSION: Adjusted comparisons demonstrated significantly improved outcomes for amivantamab versus RWCP, highlighting the value of amivantamab in addressing unmet need in patients with advanced EGFR Exon20ins NSCLC following platinum-based therapy. TRIAL REGISTRATION: CHRYSALIS: NCT02609776.

On the use of Hirshfeld surfaces for estimating atomic charges in ionic species: crystal structure of the natural ilmenite (Mg0.4168Fe0.5832)TiO3.

We performed an analysis by single-crystal X-ray diffraction and scanning electron microscopy (SEM), aiming to solve and refine the structure of an ilmenite single crystal [(Fe0.5832Mg04168)TiO3] from the city of Ouvidor (Goiás, Brazil). Hirshfeld partition was used to explore the values of w(r), dnorm and curvedness that achieve complementary surfaces for neighbouring atoms in this ionic system, and the subsequent impact on the charge distribution, allowing the ionic radius and the charges of the ilmenite sample to be modelled.

What the radiologist should know about the role of percutaneous gastrostomy: a pictorial essay.

The image-guided gastrostomy techniques, as transoral and transabdominal, can be performed when there is a failure of the endoscopic procedure or in some specific clinical scenarios. This pictorial essay intends to show the percutaneous gastrostomy techniques, indications, technical approaches, post-procedure care, and complications.

As técnicas de gastrostomia guiadas por imagem, por via transoral e transabdominal podem ser realizadas quando há falha na técnica endoscópica ou em cenários clínicos em que a endoscopia não pode ser realizada. Este ensaio iconográfico pretende mostrar as técnicas de gastrostomia percutânea, suas indicações, aspectos técnicos, cuidados pós-procedimento e complicações.