Synthesis and design of Ag-Fe bimetallic nanoparticles as antimicrobial synergistic combination therapies against clinically relevant pathogens.

The inappropriate use of antibiotics and the inadequate control of infections have led to the emergence of drug-resistant strains. In recent years, metallo-pharmaceutics and metallic nanoparticles have been proposed as potential alternative antimicrobials due to their broad-spectrum antimicrobial properties. Moreover, recent findings have shown that combinations of transition metal compounds can exhibit synergistic antimicrobial properties. Therefore, the synthesis and design of bimetallic nanoparticles is a field worth exploring to harness the interactions between groups of metals and organic complex structures found in different microbial targets, towards the development of more efficient combinatorial antimicrobials composed of synergistic metals. In this study, we present a green synthesis of Ag-Fe bimetallic nanoparticles using an aqueous extract from the leaves of Gardenia jasminoides. The characterization of the nanoparticles demonstrated that the synthesis methodology produces homogenously distributed core-shell Ag-Fe structures with spherical shapes and average diameter sizes of 13 nm (± 6.3 nm). The Ag-Fe bimetallic nanoparticles showed magnetic and antimicrobial properties; the latter were evaluated against six different, clinically relevant multi-drug-resistant microbial strains. The Ag-Fe bimetallic nanoparticles exhibited an antimicrobial (bactericidal) synergistic effect between the two metals composing the bimetallic nanoparticles compared to the effects of the mono-metallic nanoparticles against yeast and both Gram-positive and Gram-negative multidrug-resistant bacteria. Our results provide insight towards the design of bimetallic nanoparticles, synthesized through green chemistry methodologies, to develop synergistic combinatorial antimicrobials with possible applications in both industrial processes and the treatment of infections caused by clinically relevant drug-resistant strains.

Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.

Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Use of sequential-batch fermentations to characterize the impact of mild hypothermic temperatures on the anaerobic stoichiometry and kinetics of Saccharomyces cerevisiae.

This work presents a characterization of the stoichiometry and kinetics of anaerobic batch growth of Saccharomyces cerevisiae at cultivation temperatures between 12 and 30°C. To minimize the influence of the inoculum condition and ensure full adaptation to the cultivation temperature, the experiments were carried out in sequencing batch reactors. It was observed that the growth rate obtained in the first batch performed after each temperature shift was 10-30% different compared with the subsequent batches at the same temperature, which were much more reproducible. This indicates that the sequencing batch approach provides accurate and reproducible growth rate data. Data reconciliation was applied to the measured time patterns of substrate, biomass, carbon dioxide and byproducts with the constraint that the elemental conservation relations were satisfied, allowing to obtain consistent best estimates of all uptake and secretion rates. Subsequently, it was attempted to obtain an appropriate model description of the temperature dependency of these rates. It was found that the Ratkowsky model provided a better description of the temperature dependency of growth, uptake and secretion rates than the Arrhenius law. Most interesting was to find that most of the biomass-specific rates have the same temperature dependency, leading to a near temperature independent batch stoichiometry.

A candidate gene study of antiepileptic drug tolerability and efficacy identifies an association of CYP2C9 variants with phenytoin toxicity.

BACKGROUND AND PURPOSE: It is widely acknowledged that individual response to antiepileptic drugs (AEDs) is influenced by genetic factors. However, most of the underlying genes and genetic variants remain unidentified to date. The purpose of this study is to examine the role of common variants in a number of candidate genes in the response to commonly prescribed AEDs. METHODS: We recruited 495 patients with epilepsy. Patients were classified according to their response to several AEDs. We genotyped 104 polymorphisms in 17 candidate genes for AED response. We looked for statistically significant associations between these polymorphisms and well-defined AED response phenotypes. RESULTS: We identified significant associations of CYP2C9 variant alleles with presence of phenytoin (PHT) adverse drug reactions (ADRs) and of GSTM1 copy number variation with the presence of carbamazepine ADRs. The latter association could not be confirmed in a replication study. CONCLUSIONS: Our study is the first comprehensive candidate gene association study in epilepsy pharmacogenetics. Our results confirm the role of CYP2C9 variants in PHT toxicity. No other definite associations were identified. Large-scale efforts are needed to unravel the genetic determinants of AED response.

Effect of histological processing and methacrylate sectioning on the area of gill tissue in teleost.

Deformation of biological tissues may occur during histological processing and results in loss of accuracy when quantitative information about cells, tissues and organs is necessary. In this study, the gill tissue from armored catfish (Pterygoplichthys anisitsi) was quantified in each step of processing using the stereological principles. During processing for glycol methacrylate embedding, gill tissue from shrinks significantly but regains its original dimensions after sectioning.

Effect of histological processing and methacrylate sectioning on the area of gill tissue in teleost / Efeito do processamento histológico e seccionamento em metacrilato sobre a área de tecido branquial em teleósteo

Deformation of biological tissues may occur during histological processing and results in loss of accuracy when quantitative information about cells, tissues and organs is necessary. In this study, the gill tissue from armored catfish (Pterygoplichthys anisitsi) was quantified in each step of processing using the stereological principles. During processing for glycol methacrylate embedding, gill tissue from shrinks significantly but regains its original dimensions after sectioning.

Deformações nos tecidos podem ocorrer durante o processamento histológico e resultar em informações errôneas quando há necessidade de dados quantitativos sobre células, tecidos e órgãos. Neste estudo, o tecido branquial do cascudo (Pterygoplichthys anisitsi) foi quantificado em cada etapa do processamento utilizando os princípios de estereologia. O tecido branquial reduziu significativamente durante processamento histológico com metacrilato, mas retornou às suas dimensões iniciais depois de seccionadas, o que indica não ocorrer nenhuma perda na informação quantitativa do tecido.

Prevalencia de la incontinencia urinaria en la población femenina atendida en el área sanitaria de Alicante / Prevalence of urinary incontinence among women in the health area of Alicante (Spain)

Fundamento y objetivo. Estimar la prevalencia de la incontinencia urinaria (IU), sus características e impacto en la calidad de vida mujeres atendidas en el área sanitaria de Alicante. Pacientes y método. Estudio epidemiológico, transversal, multicéntrico, desarrollado durante un mes, en el que participaron 639 mujeres que acudieron consecutivamente a consultorios de ginecología por motivos diferentes de la IU y accedieron voluntariamente a cumplimentar una encuesta que contenía el International Consultation on Incontinence Questionnaire. Se recogió información referente a la frecuencia, cantidad y afectación. Se analizó la posible relación de diferentes factores con la gravedad. Resultados. El 39,97% reconocía tener IU; la más frecuente fue la de esfuerzo (IUE) (72,53%). La IUE fue más frecuente en el grupo de mayor edad (p < 0,001). Se observó mayor afectación en la calidad de vida en el grupo de menor edad, aunque la diferencia no fue significativa. La mayoría (77,25%) presentó gravedad leve y en general (63,95%) tenían pequeñas pérdidas. Menos del 16% refirió algún tratamiento para la IU. La gravedad se correlacionó con pérdidas «al esfuerzo», «continua» y «sin motivo evidente», así como con la IU de tipo IUU e IUM. Conclusiones. El 40% de las mujeres que acuden a los consultorios de ginecología de nuestro entorno presentan IU, la mayoría tipo IUE. La IU de mayor severidad, según el ICIQ-SF, apenas afecta al 11% de los casos, no se relaciona con la edad y sí con ciertos tipos de pérdida (AU)

Background and objective. To estimate the prevalence and characteristics of urinary incontinence (UI) and its effects on quality of life in women in the health area of Alicante. Patients and method. We performed an epidemiological, cross sectional, multicenter study over a 1-month period in 639 women who consecutively attended the gynecology clinic for reasons other than UI and who voluntarily agreed to participate in a survey that included the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). Information on the frequency and quantity, as well as on the effects of UI, was gathered. The possible association of several factors with severity was analyzed. Results. A total of 39.97% of the women reported having UI. The most frequent type of UI was stress incontinence (SUI). Quality of life was more adversely affected in younger women, although this difference was not significant. The severity of UI was mild in 77.25% of the women and urine leaks were small in 63.95%. Less than 16% reported having treatment for UI. Severity was correlated with stress leaks, continuous leaks and leaks with no apparent cause, as well as with SUI and mixed urinary incontinence. Conclusions. Forty percent of the women attending the gynecology clinic in our environment had UI, mostly SUI. The most severe UI, according to the ICIQ-SF, affected only 11% of patients with UI and was associated with certain types of leakage but not with age (AU)

Persistent cerebrovascular changes in postpartum preeclamptic women: a Doppler evaluation.

OBJECTIVE: Our goal was to evaluate the cerebral vasculature in postpartum normotensive and preeclamptic women. STUDY DESIGN: Nineteen previously preeclamptic women and 19 matched normotensive controls were studied at 6 weeks, and 8 preeclamptic women and 28 normotensive controls were studied at 12 weeks post partum. Systolic, diastolic, and mean velocities, as well as resistance and pulsatility indexes, of the middle cerebral, ophthalmic, and central retinal arteries were recorded. Data are presented as median and range. Statistical significance was set at p < 0.05. RESULTS: There were no differences in maternal age, parity, heart rate, mean arterial pressure, and proteinuria between the two groups at 6 and 12 weeks post partum. At 6 weeks post partum the preeclamptic group had higher ophthalmic artery diastolic velocity (9.0 cm/sec, 3.1 to 22.3, vs 5.4 cm/sec, 3.0 to 20.1; p = 0.008), ophthalmic artery mean velocity (6.0 cm/sec, 8.8 to 34.8, vs 12.5 cm/sec, 6.8 to 35.4; p = 0.03), and central retinal artery systolic velocity (10.0 cm/sec, 7.6 to 28.0, vs 8.4 cm/sec, 5.2 to 18.3; p = 0.02). The ophthalmic artery resistance index (0.72, 0.43 to 0.88, vs 0.79, 0.66 to 0.90; p = 0.03) and ophthalmic artery pulsatility index (1.56, 0.94 to 2.82, vs 2.03, vs 1.13 to 3.10; p = 0.04) were lower in the preeclamptic group. At 12 weeks post partum the preeclamptic group had elevated ophthalmic artery mean velocity (14.5 cm/sec, 7.9 to 20.2, vs 10.9 cm/sec, 5.5 to 15.4 p = 0.01), central retinal artery systolic velocity (11.1 cm/sec, 6.8 to 15.9, vs 8.5, 5.1 to 15.3; p = 0.02), and central retinal artery diastolic velocity (3.9 cm/sec, 1.2 to 5.2, vs 3.0, 1.4 to 5.8; p < 0.05). CONCLUSION: In the postpartum period preeclamptic women show persistently elevated central retinal artery systolic velocity, which suggests distal vasoconstriction.

Elevated concentrations of plasma omega-3 polyunsaturated fatty acids among Alaskan Eskimos.

Eskimos living in rural southwestern Alaska depend on fish and marine mammals as major sources of subsistence food. Fatty acid concentrations in 80 Yupik Eskimos living in either a coastal or river village of southwestern Alaska were compared with those of non-Native control subjects. Concentrations of total plasma omega-3 fatty acids, eicosapentaenoic acid (20:5 omega-3), and docosahexaenoic acid (22:6 omega-3) were 4.3, 13, and 6.8 times higher, respectively, in Native participants than in non-Native control subjects. Concentrations of these fatty acids were higher in coastal-village than in river-village participants; concentrations paralleled consumption of marine mammal oil and marine fish. The ratios of eicosapentaenoic to arachidonic acid for adult coastal- and river-village participants were 1.16 and 0.70, respectively, 14 and 9 times those of non-Native adults, respectively. There was no increase in the mean bleeding times of Native participants of either village.