In Vitro Antimicrobial Studies of Mesoporous Silica Nanoparticles Comprising Anionic Ciprofloxacin Ionic Liquids and Organic Salts.

The combination of active pharmaceutical ingredients in the form of ionic liquids or organic salts (API-OSILs) with mesoporous silica nanoparticles (MSNs) as drug carriers can provide a useful tool in enhancing the capabilities of current antibiotics, especially against resistant strains of bacteria. In this publication, the preparation of a set of three nanomaterials based on the modification of a MSN surface with cholinium ([MSN-Chol][Cip]), 1-methylimidazolium ([MSN-1-MiM][Cip]) and 3-picolinium ([MSN-3-Pic][Cip]) ionic liquids coupled with anionic ciprofloxacin have been reported. All ionic liquids and functionalized nanomaterials were prepared through sustainable protocols, using microwave-assisted heating as an alternative to conventional methods. All materials were characterized through FTIR, solution 1H NMR, elemental analysis, XRD and N2 adsorption at 77 K. The prepared materials showed no in vitro cytotoxicity in fibroblasts viability assays. The minimum inhibitory concentration (MIC) for all materials was tested against Gram-negative K. pneumoniae and Gram-positive Enterococcus spp., both with resistant and sensitive strains. All sets of nanomaterials containing the anionic antibiotic outperformed free ciprofloxacin against resistant and sensitive forms of K. pneumoniae, with the prominent case of [MSN-Chol][Cip] suggesting a tenfold decrease in the MIC against sensitive strains. Against resistant K. pneumoniae, a five-fold decrease in the MIC was observed for all sets of nanomaterials compared with neutral ciprofloxacin. Against Enterococcus spp., only [MSN-1-MiM][Cip] was able to demonstrate a slight improvement over the free antibiotic.

Novel Organic Salts Based on Mefloquine: Synthesis, Solubility, Permeability, and In Vitro Activity against Mycobacterium tuberculosis.

The development of novel pharmaceutical tools to efficiently tackle tuberculosis is the order of the day due to the rapid development of resistant strains of Mycobacterium tuberculosis. Herein, we report novel potential formulations of a repurposed drug, the antimalarial mefloquine (MFL), which was combined with organic anions as chemical adjuvants. Eight mefloquine organic salts were obtained by ion metathesis reaction between mefloquine hydrochloride ([MFLH][Cl]) and several organic acid sodium salts in high yields. One of the salts, mefloquine mesylate ([MFLH][MsO]), presented increased water solubility in comparison with [MFLH][Cl]. Moreover, all salts with the exception of mefloquine docusate ([MFLH][AOT]) showed improved permeability and diffusion through synthetic membranes. Finally, in vitro activity studies against Mycobacterium tuberculosis revealed that these ionic formulations exhibited up to 1.5-times lower MIC values when compared with [MFLH][Cl], particularly mefloquine camphorsulfonates ([MFLH][(1R)-CSA], [MFLH][(1S)-CSA]) and mefloquine HEPES ([MFLH][HEPES]).

Exploiting the antiproliferative potential of spiropyrazoline oxindoles in a human ovarian cancer cell line.

Cancer is still one of the deadliest diseases worldwide despite the efforts in its early detection and treatment strategies. However, most chemotherapeutic agents still present side effects in normal tissues and acquired resistance that limit their efficacy. Spiropyrazoline oxindoles might be good alternatives as they have shown antiproliferative activity in human breast and colon cancer cell lines, without eliciting cytotoxicity in healthy cells. However, their potential for ovarian cancer was never tested. In this work, the antiproliferative activity of five spiropyrazoline oxindoles was assessed in ovarian cancer cells A2780 and the biological targets and mechanism of action of the most promising compound evaluated. Compound 1a showed the highest antiproliferative effect, as well as the highest selectivity for A2780 cells compared to healthy fibroblasts. This antiproliferative effect results from the induction of cell death by mitochondria-mediated apoptosis and autophagy. In vitro DNA interaction studies demonstrated that 1a interacts with DNA by groove-binding, without triggering genotoxicity. In addition, 1a showed a strong affinity to bovine serum albumin that might be important for further inclusion in drug delivery platforms. Proteomic studies reinforced 1a role in promoting A2780 endoplasmatic reticulum (ER) stress by destabilizing the correct protein folding which triggers cell death via apoptosis and autophagy.

A novel Ehrlichia strain (Rickettsiales: Anaplasmataceae) detected in Amblyomma triste (Acari: Ixodidae), a tick species of public health importance in the Southern Cone of America.

The aim of this work was to report the detection of a putative novel Ehrlichia strain associated with the tick Amblyomma triste. Free-living adult ticks determined as A. triste were collected by drag-sampling in Argentina and Uruguay. Molecular detection of Ehrlichia agents was performed targeting three different loci: 16S rRNA gene, dsb gene and a fragment of groESL heat shock operon. In total, 164 adults of A. triste (38 from INTA E.E.A Delta del Paraná in Argentina and 126 from Toledo Chico in Uruguay) were analyzed. One tick (0.6%) collected in INTA E.E.A. Delta del Paraná (Argentina) was positive. The phylogenetic analyses show that the Ehrlichia strain found in this study (named Ehrlichia sp. strain Delta) represents an independent lineage within the genus Ehrlichia, close to E. chaffeensis and E. muris. This is also the first report of an Ehrlichia agent infecting the tick A. triste. The medical and veterinary significance of Ehrlichia sp. strain Delta remains to be demonstrated. However, it is important to mention that adults of A. triste are aggressive to humans and domestic mammals. Therefore, the potential role of A. triste in the transmission of Ehrlichia agents to humans or domestic animals across its distributional range should be highlighted, even more considering that Ehrlichia sp. strain Delta is phylogenetically related to the zoonotic E. chaffeensis, which is recognized as pathogenic to both humans and animals.

Synthesis and Antibacterial Activity of Ionic Liquids and Organic Salts Based on Penicillin G and Amoxicillin hydrolysate Derivatives against Resistant Bacteria.

The preparation and characterization of ionic liquids and organic salts (OSILs) that contain anionic penicillin G [secoPen] and amoxicillin [seco-Amx] hydrolysate derivatives and their in vitro antibacterial activity against sensitive and resistant Escherichia coli and Staphylococcus aureus strains is reported. Eleven hydrolyzed ß-lactam-OSILs were obtained after precipitation in moderate-to-high yields via the neutralization of the basic ammonia buffer of antibiotics with different cation hydroxide salts. The obtained minimum inhibitory concentration (MIC) data of the prepared compounds showed a relative decrease of the inhibitory concentrations (RDIC) in the order of 100 in the case of [C2OHMIM][seco-Pen] against sensitive S. aureus ATCC25923 and, most strikingly, higher than 1000 with [C16Pyr][seco-Amx] against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. These outstanding in vitro results showcase that a straightforward transformation of standard antibiotics into hydrolyzed organic salts can dramatically change the pharmaceutical activity of a drug, including giving rise to potent formulations of antibiotics against deadly bacteria strains.

Corrigendum: A Novel Small Molecule p53 Stabilizer for Brain Cell Differentiation.

[This corrects the article DOI: 10.3389/fchem.2019.00015.].

A Novel Small Molecule p53 Stabilizer for Brain Cell Differentiation.

Brain tumor, as any type of cancer, is assumed to be sustained by a small subpopulation of stem-like cells with distinctive properties that allow them to survive conventional therapies and drive tumor recurrence. Thus, the identification of new molecules capable of controlling stemness properties may be key in developing effective therapeutic strategies for cancer by inducing stem-like cells differentiation. Spiropyrazoline oxindoles have previously been shown to induce apoptosis and cell cycle arrest, as well as upregulate p53 steady-state levels, while decreasing its main inhibitor MDM2 in the HCT116 human colorectal carcinoma cell line. In this study, we made modifications in this scaffold by including combinations of different substituents in the pyrazoline ring in order to obtain novel small molecules that could modulate p53 activity and act as differentiation inducer agents. The antiproliferative activity of the synthesized compounds was assessed using the isogenic pair of HCT116 cell lines differing in the presence or absence of the p53 gene. Among the tested spirooxindoles, spiropyrazoline oxindole 1a was selective against the cancer cell line expressing wild-type p53 and presented low cytotoxicity. This small molecule induced neural stem cell (NSC) differentiation through reduced SOX2 (marker of multipotency) and increased ßIII-tubulin (marker of neural differentiation) which suggests a great potential as a non-toxic inducer of cell differentiation. More importantly, in glioma cancer cells (GL-261), compound 1a reduced stemness, by decreasing SOX2 protein levels, while also promoting chemotherapy sensitization. These results highlight the potential of p53 modulators for brain cell differentiation, with spirooxindole 1a representing a promising lead molecule for the development of new brain antitumor drugs.

Decomposition techniques with mixed integer programming and heuristics for home healthcare planning.

We tackle home healthcare planning scenarios in the UK using decomposition methods that incorporate mixed integer programming solvers and heuristics. Home healthcare planning is a difficult problem that integrates aspects from scheduling and routing. Solving real-world size instances of these problems still presents a significant challenge to modern exact optimization solvers. Nevertheless, we propose decomposition techniques to harness the power of such solvers while still offering a practical approach to produce high-quality solutions to real-world problem instances. We first decompose the problem into several smaller sub-problems. Next, mixed integer programming and/or heuristics are used to tackle the sub-problems. Finally, the sub-problem solutions are combined into a single valid solution for the whole problem. The different decomposition methods differ in the way in which sub-problems are generated and the way in which conflicting assignments are tackled (i.e. avoided or repaired). We present the results obtained by the proposed decomposition methods and compare them to solutions obtained with other methods. In addition, we conduct a study that reveals how the different steps in the proposed method contribute to those results. The main contribution of this paper is a better understanding of effective ways to combine mixed integer programming within effective decomposition methods to solve real-world instances of home healthcare planning problems in practical computation time.

[Functional results of two different surgical approaches in patients with distal humerus fractures type C (AO)]. / Resultados funcionales de dos abordajes quirúrgicos en pacientes con fractura de húmero distal tipo C (AO).

INTRODUCTION: The fractures of distal humerus present a world incidence of the 2%, stiff and painful joints are common consequences of these injuries. We used two surgical approaches for the treatment of these fractures, one with olecranon osteotomy and one with triceps split. OBJECTIVE: To compare the functional results in patients with fractures AO type C treated surgically by means of both approaches. MATERIALS AND METHODS: A retrolective, observational, comparative study in patients with distal humerus fracture AO type C diagnosis. We used the elbow functional scale of our unit for measuring clinical status. We compared the results of consolidated fractures of patients from 18 to 65 years old treated with osteosynthesis in the period from March 2002 through February 2004. RESULTS: Nineteen patients were included (11 women and 8 men), mean age of 49.3. Triceps split approach: t: 1 patient (8.4%) had excellent, 2 good (16.6%), 4 regular (33.4%) and 5 poor (41.6%) results; for the olecranon osteotomy approach 7 poor results were found (p = 0.2270 exact fisher's test). DISCUSSION: Were found clinically better functional outcome in patients treatment with of triceps split, was not found statistical significance this was because the size of the groups and the clinical scale score that was used in this unit. CONCLUSIONS: We recommend the utilization of the approach of triceps split by presenting better functional results.

Melhoria na qualidade da saúde materno-infantil no Município de Manicoré - AM, no período de 2001 to 2004 / Improvement of quality for child and maternal health in the city of Manicoré - AM, from 2001 to 2004

Este artigo é resultado de uma pesquisa sobre um passado recente na vida dos cidadãos Manicorenses e a realidade vivida hoje pela população. Depois da ativação do Hospital Maternidade Pública Manicorense local, a qualidade de vida dos cidadãos mudou quase que repentinamente. Foi relevante a atuação dos órgãos públicos municipais nas pessoas do Secretário Municipal de Saúde e do Prefeito da cidade. Houve avanço na qualidade de vida do cidadão, servindo como referência e bom exemplo para outras cidades da região. O conteúdo do artigo revela como a atuação do Estado em nível municipal (Manicoré) foi importante para a implantação de políticas públicas com participação das comunidades locais. Estas conheciam quais suas necessidades e o Estado foi apenas intermediário. Foram implantados projetos para treinamento, tendo-se observado incremento na qualidade de vida das comunidades ribeirinhas de Manicoré

Uso de anestésicos locais em gestantes / The use of local anesthetics in pregnancy

Os autores fazem uma breve revisäo da literatura sobre o uso de anestésicos locais em pacientes gestantes, com o objetivo de demonstrar aos cirurgiöes-dentistas quais säo as soluçöes anestésicas e quais säo os vasoconstritores mais indicados para anestesia local nestas pacientes

Osteorradionecrose: o que é, como prevenir e como tratar? / Osteoradionecrosis: what is and how to forewarn and treat this?

Os autores fazem uma discussäo sobre a literatura pesquisada, enfocando a osteorradionecrose: o que é, quais os fatores que predispöe o seu surgimento, como prevení-lo e quais as alternativas de tratamento para a infecçäo já instalada

Expansäo rápida da maxila assistida cirurgicamente: revisäo de literatura / Rapid maxillary expansion with surgical assistence: literature review

Neste artigo, foi realizado uma revisäo da literatura sobre expansäo rápida da maxila assistida cirurgicamente na qual foram discutidos as indicaçöes, contra-indicaçöes, técnicas cirúrgicas e alteraçöes na maxila e estruturas anexas

Comparativo no tratamento de fraturas baixas de côndilo com uma ou duas osteossínteses à fio de aço / Comparative in the treatment of low fractures of condyle with one or two osteosynthesis in steel string

Os autores relatam um estudo realizado em 22 pacientes que apresentavam fraturas de côndilo, sendo que destes, 18 apresentavam fraturas unilaterais e 4 fraturas bilaterais, totalizando 26 fraturas. O tratamento cirúrgico foi realizado com fixação com fio de aço com uma osteossíntese (14 fraturas), e com duas osteossínteses (12 fraturas). Através de uma avaliação radiográfica pós-operatório destes pacientes, observou-se um melhor resultado nos casos onde foram utilizadas duas osteossínteses

Conduta cirúrgica em fratura bilateral de mandíbula atrófica em paciente senil edêntulo: relato de caso / Surgical conduct in bilateral fracture of atrophy mandible in senile patient: relate of case

Os autores relatam um caso de fratura de mandíbula atrófica bilateral, em paciente senil edêntulo, com envolvimento de colo de côndilo do lado esquerdo e corpo mandibular do lado direito. Há uma grande controvérsia entre os autores quanto ao melhor tratamento para estes casos, se a reduçäo fechada (incruenta) ou a reduçäo aberta (cruenta). Propomos para estes casos de fraturas bilaterais, um método de tratamento eficiente e de baixo custo, que consiste em reduçäo aberta com osteossíntese à fio de aço e cerclagem mandibular, suspensäo da prótese superior e bloqueio maxilo-mandibular, onde os resultados de uma reduçäo anatômica das fraturas, säo mais favoráveis, principalmente, do ponto de vista funcional

Psicopatologia Geral de Karl Jaspers: metodologia de estudo / General Psychopathology by Karl Jaspers: study's methodology

O autor descreve um método de estudo do livro Psicopatologia Geral de Karl Jaspers, desenvolvido ao longo dos últimos sete anos (1985-1992), voltado ao ensino de Psicopatologia para Médicos Residentes de Psiquiatria. Constata que a análise do livro Psicopatologia Geral em forma de seminários, em conjugaçäo com o Sistema AMDP e associado a entrevistas psiquiátricas ilustrativas, demonstrou ser um método eficiente no processo de aprendizagem de psicopatologia ao possibilitar aos Médicos Residentes o incremento das faculdades de observar, perguntar, analisar e pensar em psicopatologia. Ao concluir, aponta a importância de Karl Jaspers na psiquiatria do século XX, cujo paradigma fenomenológico tem sua origem no livro Psicopatologia Geral, o qual permanece como uma fonte sempre atual de conhecimentos

Psicopatologia Geral de Karl Jaspers: metodologia de estudo

O autor descreve um metodo de estudo do livro Psicopatologia Geral de Karl Jaspers, desenvolvido ao longo dos ultimos sete anos (1985-1992), voltando ao ensino de Psicopatologia para Medicos Residentes de Psiquiatria. Constata que a analise do livro Psicopatologia Geral em forma de seminarios, em conjugacao com o Sistema AMDP e associado a entrevistas psiquiatricas ilustrativas, demonstrou ser um metodo eficiente no processo de aprendizagem de psicopatologia ao possibilitar aos Medicos Residentes o incremento das faculdades de observar, perguntar, analisar e pensar em psicopatologia. Ao concluir, aponta a importancia de Karl Jaspers na psiquiatria do seculo XX, cujo paradigma fenomenologico tem sua origem no livro Psicopatologia Geral, o qual permanece como uma fonte sempre atual de conhecimentos.

Psicopatologia geral de Karl Jaspers: metodologia de estudo / General psychopathology Karl Jaspers: study methodology

O autor descreve um método de estudo do livro Psicopatologia Geral de Karl Jaspers, desenvolvido ao longo dos últimos sete anos (1985 - 1992), voltado ao ensino de Psicopatologia para Médicos Residentes de Psiquiatria.Constata que a análise do livro Psicopatologia Geral em forma de seminários, em conjugação com o Sistema AMDP e associado a entrevistas psiquiátricas ilustrativas, demonstrou ser um método eficiente no processo de aprendizagem de psicopatologia ao possibilitar aos Médicos Residentes o incremento das faculdades de observar, perguntar, analisar e pensar em psicopatologia.Ao concluir, aponta a importância de Karl Jaspers na psiquiatria do século XX, cujo paradigma fenomenológico tem sua origem no livro Psicopatologia Geral, o qual permanece como uma fonte sempre atual de conhecimentos

Psicopatologia geral de Karl Jaspers: metodologia de estudo

O autor descreve um metodo de estudo do livro Psicopatologia Geral de Karl Jaspers, desenvolvido ao longo dos ultimos sete anos (1985-1992), voltado ao ensino de Psicopatologia para Medicos Residentes de Psiquiatria. Constata que a analise do livro Psicopatologia Geral em forma de seminarios, em conjugacao com o Sistema AMDP e associado a entrevistas psiquiatricas ilustrativas, demonstrou ser um metodo eficiente no processo de aprendizagem de psicopatologia ao possibilitar aos Medicos Residentes o incremento das faculdades de observar, perguntar, analisar e pensar em psicopatologia. Ao concluir, aponta a importancia de Karl Jaspers na psiquiatria do seculo XX, cujo paradigma fenomenologico tem sua origem no livro Psicopatologia Geral, o qual permanece como uma fonte sempre atual de conhecimentos.

Origem e desenvolvimento dos Arquivos de Saúde Mental do Estado de Säo Paulo / Origin and development of the São Paulo State Mental Health Archives

O autor apresenta um breve histórico acerca da origem e do desenvolvimento dos "Arquivos de Saúde Mental do Estado de Säo Paulo", desde sua criaçäo como "Memórias dps Hospícios de Juquery", em 1924, até o presente, 1986, como "Arquivos de saúde Mental do Estado de Säo paulo". Veículo de expresso do pensamento científico do corpo clínico do Hospital de Juqueri, revista transformou-se numa das principais fontes da memória científica da psiquiatria paulista, retratando o desenvolvimento da psiquiatria, em Säo Paulo, nos últimos sessenta anos