Toxicological Investigation and Antinociceptive Property of Potassium Thiophene‐3‐Trifluoroborate

Abstract: The aim of the present study was to evaluate pharmacological and toxicological properties of potassium thiophene‐3‐trifluoroborate (RBF₃K). The acute effect of RBF₃K was evaluated on mice. To this end, mice received a single dose of RBF₃K (25, 50, and 100 mg/kg, by oral route, p.o.) and after 72 hrs, blood, liver, and kidney samples were collected. δ‐Aminolevulinate dehydratase, catalase and glutathione‐S‐transferase activities, thiobarbituric acid‐reactive substances and vitamin C levels, as well as plasma aspartate and alanine aminotransferase activities and creatinine levels were determined. Hepatic and renal lipid peroxidation levels in treated mice did not differ from those in control mice. No significant differences between treated and control mice were detected in hepatic and renal δ‐aminolevulinate dehydratase activity. Aspartate and alanine aminotransferase activities as well as urea and creatinine levels were similar among the groups. In contrast, results obtained from in vivo experiments revealed that RBF₃K, orally administered, reduced peritoneovisceral pain induced by acetic acid administered i.p. Doses of 1, 5, 10, 25, 50, and 100 mg/kg of RBF₃K were assessed in the antinociceptive investigation and the effect was significantly different than control groups from 5 mg/kg. It was observed that α_2‐adrenergic and serotonergic, but not opioidergic, receptors appear to be involved in orally administered RBF₃K. Mice treated with RBF₃K did not reveal any motor impairment in the open field. This is a promising compound for more detailed pharmacological studies involving organotrifluoroborate compounds.     

Blood laboratory testing for early prediction of preeclampsia: chasing the finish line or at the starting blocks?

Preeclampsia (PE) affects 2–8% of pregnancies worldwide, thus representing an important cause of maternal and neonatal morbidity, up to death. Many studies have been designed to identify putative biomarkers for accurate and timely diagnosing PE, but only some of them were focused on specific and sensitive biomarkers for early prediction of this life-threatening condition. In particular, some prospective studies aimed to investigate the predictive role of circulating biomarkers before 20 weeks of gestation in the general pregnant population yielded conflicting results. This article is hence centered on results obtained in studies investigating the predictive performances of angiogenic, anti-angiogenic, inflammatory, endocrine, and epigenetic biomarkers. The available evidence suggests that angiogenic and anti-angiogenic molecules, in particular the sFlt1:PlGF ratio, may be considered the biomarkers with the best diagnostic performance in the second trimester. However, doubts remain about their use in clinical settings before the 20th gestational week. Even lower evidence is available for other biomarkers, due to the fact that some positive results have not been confirmed in ensuing investigations, whereas unresolved analytical issues still contribute to make their clinical reliability rather questionable. Differential expression of microRNAs seems also a promising evidence for early prediction of PE, but additional research and well-designed prospective studies are needed to identify and validate routine predictive tests.

• KEY MESSAGES

• Preeclampsia affects 2–8% of pregnant women worldwide, thus remaining one of the leading causes of maternal and neonatal morbidity and mortality.

• Several studies have investigated the predictive role of circulating biomarkers before 20th week of gestation with conflicting results.

• Additional research and well-designed prospective studies are needed to identify and validate predictive tests in clinical practice.

     

Connexin 26 enhances the bystander effect in HSVtk/GCV gene therapy for human bladder cancer by adenovirus/PLL/DNA gene delivery

Herpes simplex thymidine kinase/ganciclovir (HSVtk/GCV) gene therapy has been used for the treatment of a variety of cancers. Its efficacy is enhanced by the bystander effect that helps overcome the delivery problems commonly observed in current gene therapy. Connexins encode proteins that produce gap junctions, which enable intercellular communication and the bystander effect. We previously demonstrated that decreased Cx 26 expression and loss of gap junctional intercellular communication were associated with human bladder cancer. To investigate the efficacy of the bystander effect in HSVtk/GCV gene therapy, the Cx 26 gene was introduced into UM-UC-3 and UM-UC-14 bladder cancer cell lines by an adenovirus poly-L-lysine conjugate using a multigenic expression plasmid that expressed both the HSVtk and Cx 26 genes. We found significantly increased cytotoxicity in HSVtk/GCV gene therapy after introduction of the HSVtk and Cx 26 genes together compared with the cytotoxicity seen after introduction of the HSVtk gene and LacZ genes in vitro and in vivo. Cytotoxicity correlated with Cx 26 expression and the induction of functional gap junctions. This study indicates that combination gene therapy with co-expression of the HSVtk and Cx 26 genes potentiates HSVtk/GCV gene therapy through the bystander effect.     

Cefoperazone compared with chloramphenicol in the treatment of typhoid fever

The authors have conducted an open randomized study to compare the clinical efficacy and safety of cefoperazone with those of chloramphenicol in the treatment of typhoid fever. They studied 56 subjects (28 in each group), 36 males and 20 females, whose average age was 25.9 years. The diagnosis of typhoid fever was made when one of the at least three blood cultures performed was positive for Salmonella typhi and in the presence of a 'toxic'-like symptomatology and hyperpyrexia (39 degrees C). Moreover, several stool cultures were done and the signs and symptoms characteristic of the pathology in progress were monitored. Furthermore, the MICs of cefoperazone and chloramphenicol were determined for all the strains of S. typhi isolated in both groups. Cefoperazone was given at the mean dose of 2 g i.v. every 8 h, and chloramphenicol at the dose of 500 mg by oral route every 6 h. The results obtained were assessed statistically (Friedman's test and Fischer's test). The authors conclude that cefoperazone is as active as chloramphenicol, and the importance of this result should not be underestimated.     

Real-World Effectiveness and Safety of a Live-Attenuated Herpes Zoster Vaccine: A Comprehensive Review

Herpes zoster (HZ) is a common, painful and debilitating disease caused by the reactivation of latent varicella-zoster virus in ganglia. This clinical event occurs more frequently in the elderly and those who are immunocompromised. The most common complication of HZ is post-herpetic neuralgia (PHN) which is responsible for the highest HZ-related burden of illness and is challenging to treat. Due to the important clinical and economic impact of HZ and PHN, and the suboptimal treatments that are currently available, HZ vaccination is an important approach to reduce the burden of illness. Currently, one-dose, live-attenuated vaccine is licensed in the United States and Europe to prevent HZ and it is included in some national immunization programs. The clinical efficacy, safety and tolerability of the vaccine has been demonstrated in two large phase III clinical trials, involving more than 38,000 and 22,000 individuals aged ≥60 and 50–59 years, respectively. This comprehensive review summarizes the extensive “real-world” effectiveness and safety data from both immunocompetent and immunocompromised individuals. These data confirm those from the clinical trials, supporting the use of HZ vaccine in clinical practice and provide evidence that the current recommendations for immunocompromised individuals should be revised. Funding: Funding for the editorial assistance, article processing charges, and open access fee for this publication was provided by Sanofi Pasteur MSD.     

Comparison of Human Denuded Amniotic Membrane and Porcine Small Intestine Submucosa as Scaffolds for Limbal Mesenchymal Stem Cells

Blinding corneal scarring is usually treated with allogeneic graft tissue. Nevertheless, the global shortage of donors leaves millions of patients in need of therapy. Traditional tissue engineering strategies involves the combination of cells, growth factors, and scaffolds that can supply cellular biological components allowing to restore the tissue function. The mesenchymal stem cells found in the limbal stroma (L-MSCs) have a self-renewal potential for multilineage differentiation. Thus, in this work we compared the potential of human amniotic membrane (hAM) and porcine small intestine submucosa (SIS) as scaffolds for L-MSCs, aiming at potential applications in corneal regeneration. For that, L-MSCs were seeded on hAM and SIS and we analyzed their viability, actin cytoskeleton, nuclei morphology, cell density, adhesion and surface markers. Our results showed that cells adhered and integrated into both membranes with a high cell density, an important characteristic for cell therapy. However, due to its transparency, the hAM allowed a better observation of L-MSCs. In addition, the analysis of surface markers expression on L-MSCs after two weeks showed a slight increase in the percentages of negative markers for MSCs grown on SIS membrane. Thus, considering a long-term culture, the hAM was considered better in maintaining the MSCs phenotype. Regarding the function as scaffolds, SIS was as efficient as the amniotic membrane, considering that these two types of biological matrices maintained the cell viability, actin cytoskeleton, nuclei morphology and mesenchymal phenotype, without causing cell death. Therefore, our data in vitro provides evidence for future pre-clinical studies were these membranes can be used as a support to transport mesenchymal stem cells to the injured area, creating a kind of temporary curative, allowing the release of bioactive molecules, such as cytokines and growth factors and then promoting the tissue regeneration, both in human and veterinary medicine.     

Tempo de validade dos exames pré‐operatórios normais para uma reintervenção cirúrgica e o impacto nos desfechos pós‐operatórios

Background and objective

There are few data defining the period of time in which preoperative tests can be considered valid. The purpose of this study was to determine the likelihood of changes in the results of preoperative tests previously normal in relation to time, and the impact of these changes on postoperative outcomes.