Pathophysiological Mechanisms In Gaseous Therapies For Severe Malaria.

Over 200 million people worldwide suffer from malaria every year, a disease that causes 584,000 deaths annually. In recent years, significant improvements have been achieved on the treatment of severe malaria, with intravenous artesunate proving superior to quinine. However, mortality remains high at 8% in children and 15% in adults in clinical trials, and even worse in the case of cerebral malaria (18% and 30%, respectively). Moreover, some individuals who do not succumb to severe malaria present long-term cognitive deficits. These observations indicate that strategies focused only on parasite killing fail to prevent neurological complications and deaths associated with severe malaria, possibly because clinical complications are associated in part with a cerebrovascular dysfunction. Consequently, different adjunctive therapies aimed at modulating malaria pathophysiological processes are currently being tested. However, none of these therapies has shown unequivocal evidence in improving patients' clinical status. Recently, key studies have shown that gaseous therapies based mainly on nitric oxide (NO), carbon monoxide (CO) and hyperbaric (pressurized) oxygen (HBO) alter vascular endothelium dysfunction and modulate host immune response to infection. Considering gaseous administration as a promising adjunctive treatment against severe malaria cases, we review here the pathophysiological mechanisms and the immunological aspects of such therapies.8

Development of dextrin-amphotericin B formulations for the treatment of Leishmaniasis

The most effective medicines available for the treatment of leishmaniasis, a life-threatening disease, exhibit serious toxicological issues. To achieve better therapeutic efficiency while decreasing toxicity associated with amphotericin B (AmB), water-soluble dextrin-AmB (Dex-AmB) formulations were developed. Self-assembled nanocomplexes were formed by dissolving Dex and AmB in alkaline borate buffer, followed by dialysis and either freeze-drying (FD) or nano spray-drying (SD), yielding water dispersible particles with a diameter of 214nm and 347nm, respectively. The very simple production process allowed the formation of amorphous inclusion complexes containing 14% of AmB in the form of monomers and water-soluble aggregates. Nanocomplexes were effective against parasites in axenic culture (IC50 of 0.056 and 0.096M for L. amazonensis and 0.030 and 0.044M for L. infantum, respectively for Dex-AmB FD and Dex-AmB SD) and in decreasing the intramacrophagic infection with L. infantum (IC50 of 0.017 and 0.023M, respectively for Dex-AmB FD and Dex-AmB SD). Also, the formulations were able to significantly reduce the cytotoxicity of AmB. Overall, this study demonstrates the suitability of dextrin as an AmB carrier and the facile and inexpensive development of a delivery system for the treatment of leishmaniasis.This work was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/ BIO/04469/2019 and BioTecNorte operation (NORTE-01-0145-FEDER000004 - Underpinning Biotechnology to foster the north of Portugal bioeconomy and NORTE-01-0145-FEDER-000012 - Structured program on bioengineered therapies for Infectious diseases and tissue regeneration) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. Ricardo Silva-Carvalho gratefully acknowledge FCT for the granted scholarship (SFRH/BD/118880/2016). Karoline Rachel Melo and Moacir Fernandes Queiroz gratefully acknowledge Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brasil for the granted scholarship.info:eu-repo/semantics/publishedVersio

Metabolic Signatures of Lung Cancer in Biofluids: NMR-Based Metabonomics of Blood Plasma

In this work, the variations in the metabolic profile of blood plasma from lung cancer patients and healthy controls were investigated through NMR-based metabonomics, to assess the potential of this approach for lung cancer screening and diagnosis. PLS-DA modeling of CPMG spectra from plasma, subjected to Monte Carlo Cross Validation, allowed cancer patients to be discriminated from controls with sensitivity and specificity levels of about 90%. Relatively lower HDL and higher VLDL + LDL in the patients' plasma, together with increased lactate and pyruvate and decreased levels of glucose, citrate, formate, acetate, several amino acids (alanine, glutamine, histidine, tyrosine, valine), and methanol, could be detected. These changes were found to be present at initial disease stages and could be related to known cancer biochemical hallmarks, such as enhanced glycolysis, glutaminolysis, and gluconeogenesis, together with suppressed Krebs cycle and reduced lipid catabolism, thus supporting the hypothesis of a systemic metabolic signature for lung cancer. Despite the possible confounding influence of age, smoking habits, and other uncontrolled factors, these results indicate that NMR-based metabonomics of blood plasma can be useful as a screening tool to identify suspicious cases for subsequent, more specific radiological tests, thus contributing to improved disease management.ERDF - Competitive Factors Thematic Operational ProgrammeFCT/PTDC/ QUI/68017/2006FCOMP-01-0124-FEDER-007439SFRH/BD/ 63430/2009National UNESCO Committee - L'Oréal Medals of Honor for Women in Science 200Portuguese National NMR Network - RNRM

Cosmological constraints from lensing statistics and supernovae on the cosmic equation of state

We investigate observational constraints from lensing statistics and high-z type Ia supernovae on flat cosmological models with nonrelativistic matter and an exotic fluid with equation of state, $p_x=(m/3 -1)\rho_x$. We show that agreement with both tests at the 68% confidence level is possible if the parameter $m$ is low ($m \lesssim 0.85$) and $0.24 \lesssim \Omega_{m0} \lesssim 0.38$ with lower values of $\Omega_{m0}$ corresponding to higher $m$. We find that a conventional cosmological constant model with $\Omega_{m0}\simeq 0.33$ is the best fit model of the combined likelihood.Comment: 7 pages, 4 postscript figures, revtex, submitted to Phys. Rev.

Day and night surgery: is there any influence in the patient postoperative period of urgent colorectal intervention?

Background Medical activity performed outside regular work hours may increase risk for patients and professionals. There is few data with respect to urgent colorectal surgery. The aim of this work was to evaluate the impact of daytime versus nighttime surgery on postoperative period of patients with acute colorectal disease. Methods A retrospective study was conducted in a sample of patients with acute colorectal disease who underwent urgent surgery at the General Surgery Unit of Braga Hospital, between January 2005 and March 2013. Patients were stratified by operative time of day into a daytime group (surgery between 8:00 and 20:59) and the nighttime group (21:00–7:59) and compared for clinical and surgical parameters. A questionnaire was distributed to surgeons, covering aspects related to the practice of urgent colorectal surgery and fatigue. Results A total of 330 patients were included, with 214 (64.8 %) in the daytime group and 116 (35.2 %) in the nighttime group. Colorectal cancer was the most frequent pathology. Waiting time (p?<?0.001) and total length of hospital stay (p?=?0.008) were significantly longer in the daytime group. There were no significant differences with respect to early or late complications. However, 100 % of surgeons reported that they are less proficient during nighttime. Conclusions Among patients with acute colorectal disease subjected to urgent surgery, there was no significant association between nighttime surgery and the presence of postoperative medical and surgical morbidities. Patients who were subjected to daytime surgery had longer length of stay at the hospital

An shRNA-Based Screen of Splicing Regulators Identifies SFRS3 as a Negative Regulator of IL-1β Secretion

The generation of diversity and plasticity of transcriptional programs are key components of effective vertebrate immune responses. The role of Alternative Splicing has been recognized, but it is underappreciated and poorly understood as a critical mechanism for the regulation and fine-tuning of physiological immune responses. Here we report the generation of loss-of-function phenotypes for a large collection of genes known or predicted to be involved in the splicing reaction and the identification of 19 novel regulators of IL-1β secretion in response to E. coli challenge of THP-1 cells. Twelve of these genes are required for IL-1β secretion, while seven are negative regulators of this process. Silencing of SFRS3 increased IL-1β secretion due to elevation of IL-1β and caspase-1 mRNA in addition to active caspase-1 levels. This study points to the relevance of splicing in the regulation of auto-inflammatory diseases

Validación del Nursing Activities Score en unidades de cuidados intensivos portuguesas

Objective: to describe the process of adaptation and validation of the Nursing Activities Score to the Portuguese context. Method: this was a pilot study of adaptation and validation of the Nursing Activities Score with a sample consisting of 67 patients hospitalized in the intensive care units of three Portuguese hospitals. The construct validity was assessed through factor analysis procedures and the internal consistency of the items was measured through the Cronbach’s alpha coeffi cient. Results: a mean workload value of 63.04% (SD = 14.25; Median = 61.30) was obtained. Psychometric data revealed a Cronbach’s alpha of 0.71 in the total scale, indicating an acceptable accuracy. Confi rmatory factor analysis suggested an appropriate adjustment between the model and the data (χ2 (199) = 214.5, p = 0.214; CFI = 0.95; RMSA = 0.035). Conclusion: in the present study, the Portuguese version of the Nursing Activities Score was found to be a valid instrument, enabling a safe assessment of the workload of nurses.Objetivo: descrever o processo de adaptação e validação do Nursing Activities Score para o contexto português. Método: trata-se de um estudo-piloto de adaptação e validação do Nursing Activities Score, com amostra de 67 doentes internados em unidades de cuidados intensivos de três hospitais portugueses. A validade de constructo avaliou-se mediante procedimentos de análise fatorial e a consistência interna dos itens através do coefi ciente Alpha de Cronbach. Resultados: obteve-se um valor médio da carga de trabalho de 63,04% (DP = 14,25; Mediana = 61,30). Os dados psicométricos revelaram um Alpha de Cronbach de 0,71, na escala total, indicando uma fi delidade aceitável. A análise fatorial confi rmatória sugeriu um ajustamento adequado entre o modelo e os dados (χ2(199) = 214,5, p = 0,214; CFI = 0,95; RMSA = 0,035). Conclusão: neste estudo, a versão portuguesa do Nursing Activities Score revelou-se um instrumento válido, permitindo avaliar a carga de trabalho dos enfermeiros com segurançaObjetivo: describir el proceso de adaptación y validación del Nursing Activities Score al contexto portugués. Método: estudio piloto de adaptación y validación del Nursing Activities Score, con muestra de 67 pacientes internados en unidades de cuidados intensivos de tres hospitales portugueses. La validez del constructo se evaluó mediante análisis factorial y por consistencia interna de los ítems evaluados a través del coefi ciente Alpha de Cronbach. Resultados: se obtuvo un valor medio de carga de trabajo de 63,04% (SD=14,25; Mediana=61,30). Los datos psicométricos expresaron un Alpha de Cronbach de 0,71 en la escala total, indicando fi delidad aceptable. El análisis factorial confi rmatorio sugirió un ajuste adecuado entre el modelo y os datos (χ2 (199)=214,5; p=0,214; CFI=0,95; RMSA=0,035). Conclusión: en este estudio, la versión portuguesa del Nursing Activities Score demostró ser un instrumento válido, permitiendo evaluar la carga de trabajo de los enfermeros con precisión

Improved Canine and Human Visceral Leishmaniasis Immunodiagnosis Using Combinations of Synthetic Peptides in Enzyme-Linked Immunosorbent Assay

Visceral leishmaniasis is endemic in many areas of tropical and subtropical America where it constitutes a significant public health problem. It is usually diagnosed by enzyme-linked immunosorbent assays (ELISA) using crude Leishmania antigens, but a variety of other immunological methods may also be applied. Although these approaches are useful, historically their sensitivity and specificity have often been compromised by the use of complex mixtures of antigens. In this context, the use of combinations of purified, well-characterized antigens appears preferable and may yield better results. In the present study, combinations of peptides derived from the previously described Leishmania diagnostic antigens A2, NH, LACK and K39 were used in ELISA against sera from 106 dogs and 44 human patients. Improved sensitivities and specificities, close to 100%, for both sera of patients and dogs was observed for ELISA using some combinations of the peptides, including the detection of VL in dogs with low anti-Leishmania antibody titers and asymptomatic infection. So, the use of combinations of B cell predicted synthetic peptides derived from antigens A2, NH, LACK and K39 may provide an alternative for improved sensitivities and specificities for immunodiagnostic assays of VL

Chromosome and DNA methylation dynamics during meiosis in autotetraploid Arabidopsis arenosa

Variation in chromosome number due to polyploidy can seriously compromise meiotic stability. In autopolyploids, the presence of more than two homologous chromosomes may result in complex pairing patterns and subsequent anomalous chromosome segregation. In this context, chromocenter, centromeric, telomeric and ribosomal DNA locus topology and DNA methylation patterns were investigated in the natural autotetraploid, Arabidopsis arenosa. The data show that homologous chromosome recognition and association initiates at telomeric domains in premeiotic interphase, followed by quadrivalent pairing of ribosomal 45S RNA gene loci (known as NORs) at leptotene. On the other hand, centromeric regions at early leptotene show pairwise associations rather than associations in fours. These pairwise associations are maintained throughout prophase I, and therefore likely to be related to the diploid-like behavior of A. arenosa chromosomes at metaphase I, where only bivalents are observed. In anthers, both cells at somatic interphase as well as at premeiotic interphase show 5-methylcytosine (5-mC) dispersed throughout the nucleus, contrasting with a preferential co-localization with chromocenters observed in vegetative nuclei. These results show for the first time that nuclear distribution patterns of 5-mC are simultaneously reshuffled in meiocytes and anther somatic cells. During prophase I, 5-mC is detected in extended chromatin fibers and chromocenters but interestingly is excluded from the NORs what correlates with the pairing patter