Assisted Knowledge Discovery for the Maintenance of Clinical Guidelines

Background

Improving antibiotic prescribing practices is an important public-health priority given the widespread antimicrobial resistance. Establishing clinical practice guidelines is crucial to this effort, but their development is a complex task and their quality is directly related to the methodology and source of knowledge used.

Objective

We present the design and the evaluation of a tool (KART) that aims to facilitate the creation and maintenance of clinical practice guidelines based on information retrieval techniques.

Methods

KART consists of three main modules 1) a literature-based medical knowledge extraction module, which is built upon a specialized question-answering engine; 2) a module to normalize clinical recommendations based on automatic text categorizers; and 3) a module to manage clinical knowledge, which formalizes and stores clinical recommendations for further use. The evaluation of the usability and utility of KART followed the methodology of the cognitive walkthrough.

Results

KART was designed and implemented as a standalone web application. The quantitative evaluation of the medical knowledge extraction module showed that 53% of the clinical recommendations generated by KART are consistent with existing clinical guidelines. The user-based evaluation confirmed this result by showing that KART was able to find a relevant antibiotic for half of the clinical scenarios tested. The automatic normalization of the recommendation produced mixed results among end-users.

Conclusions

We have developed an innovative approach for the process of clinical guidelines development and maintenance in a context where available knowledge is increasing at a rate that cannot be sustained by humans. In contrast to existing knowledge authoring tools, KART not only provides assistance to normalize, formalize and store clinical recommendations, but also aims to facilitate knowledge building.     

Dysregulation of Protease and Protease Inhibitors in a Mouse Model of Human Pelvic Organ Prolapse

Mice deficient for the fibulin-5 gene (Fbln5^−/−) develop pelvic organ prolapse (POP) due to compromised elastic fibers and upregulation of matrix metalloprotease (MMP)-9. Here, we used casein zymography, inhibitor profiling, affinity pull-down, and mass spectrometry to discover additional protease upregulated in the vaginal wall of Fbln5^−/− mice, herein named V1 (25 kDa). V1 was a serine protease with trypsin-like activity similar to protease, serine (PRSS) 3, a major extrapancreatic trypsinogen, was optimum at pH 8.0, and predominantly detected in estrogenized vaginal epithelium of Fbln5^−/− mice. PRSS3 was (a) localized in epithelial secretions, (b) detected in media of vaginal organ culture from both Fbln5^−/− and wild type mice, and (c) cleaved fibulin-5 in vitro. Expression of two serine protease inhibitors [Serpina1a (α1-antitrypsin) and Elafin] was dysregulated in Fbln5^−/− epithelium. Finally, we confirmed that PRSS3 was expressed in human vaginal epithelium and that SERPINA1 and Elafin were downregulated in vaginal tissues from women with POP. These data collectively suggest that the balance between proteases and their inhibitors contributes to support of the pelvic organs in humans and mice.     

DNA damage response signaling triggers nuclear localization of the chicken anemia virus protein Apoptin

The chicken anemia virus (CAV) protein Apoptin is a small, 13.6-kDa protein that has the intriguing activity of inducing G(2)/M arrest and apoptosis specifically in cancer cells by a mechanism that is independent of p53. The activity of Apoptin is regulated at the level of localization. Whereas Apoptin is cytoplasmic in primary cells and does not affect cell growth, in transformed cells it localizes to the nucleus, where it induces apoptosis. The properties of cancer cells that are responsible for activating the proapoptotic activities of Apoptin remain unclear. In the current study, we show that DNA damage response (DDR) signaling is required to induce Apoptin nuclear localization in primary cells. Induction of DNA damage in combination with Apoptin expression was able to induce apoptosis in primary cells. Conversely, chemical or RNA interference (RNAi) inhibition of DDR signaling by ATM and DNA-dependent protein kinase (DNA-PK) was sufficient to cause Apoptin to localize in the cytoplasm of transformed cells. Furthermore, the nucleocytoplasmic shuttling activity of Apoptin is required for DDR-induced changes in localization. Interestingly, nuclear localization of Apoptin in primary cells was able to inhibit the formation of DNA damage foci containing 53BP1. Apoptin has been shown to bind and inhibit the anaphase-promoting complex/cyclosome (APC/C). We observe that Apoptin is able to inhibit formation of DNA damage foci by targeting the APC/C-associated factor MDC1 for degradation. We suggest that these results may point to a novel mechanism of DDR inhibition during viral infection.     

Reproductive performance of the mite Brevipalpus phoenicis (Geijskes, 1939) on citrus and coffee, using life table parameters.

The flat-mite Brevipalpus phoenicis (Geijskes, 1939) (Acari: Tenuipalpidae) is considered important in citrus (Citrus spp.) and coffee plants (Coffea spp.) in Brazil, and is known as the leprosis and coffee ring spot mite, as being a vector of the Citrus Leprosis Rhabdovirus - CitLV and Coffee Ring Spot Virus - CoRSV. The objective of this work is to find out about the reproductive success of B. phoenicis on citric fruits and coffee leaves by fertility life table parameters and its biology. The experiments were carried out in laboratory conditions at 25 +/- 2 degrees C, 70 +/- 10% of relative humidity and 14 h of photophase. The lengths of embryonic and post-embryonic periods were different due to the host where the mite was reared. B. phoenicis showed better development and higher survival and fecundity in citric fruits than coffee leaves. The intrinsic rate of the population increase (r(m)) was 0.128 and 0.090 - females/female/day on citric fruits and coffee leaves, respectively. The citric fruits were more appropriate for the development of B. phoenicis than coffee leaves.     

Akrosida floribunda (Malvaceae), a new arborescent mallow from the Dominican Republic

A new species,Akrosida floribunda, is described from the Dominican Republic. This arborescent genus is now known from two species, the other beingAkrosida macrophylla, from Brazil. Both have very limited distributions.

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Resumen  Se describe la especie nuevaAkrosida floribunda de la República Dominicana. Este género arborescente actualmente se conoce de dos especies, la otraAkrosida macrophylla de Brasil. Las dos tienen distribuciones que son bien restringidas.

     

Thermal response of demersal and pelagic juvenile fishes from the surf zone during a heat‐wave simulation

Experimental measurements were collected in the laboratory to evaluate the maximum thermal limit and thermal plasticity of Neotropical juvenile fish with different life habitats (demersal and pelagic) from surf zone in response to a “heat‐wave experiment”. Trials were conducted using two temperature acclimations (T_a), including the current average temperature of Southeastern Brazil (T_a: 14 days at 25°C) and the “heat‐wave experiment” (T_a: 14 days at 30°C), simulating a heat‐wave event that occurs when the daily maximum temperature of more than five consecutive days exceeds the average maximum temperature by 5°C. Typical species of the surf zone were used: the demersal White sea catfish (Genidens barbus) and Gulf kingcroaker (Menticirrhus littoralis), and the pelagic fishes Great pompano (Trachinotus goodei) and Long‐fin mullet (Mugil brevirostris). The thermal range and plasticity values for the both life‐habitats species were verified through current and heat‐wave acclimation. The thermal tolerance at high temperatures (CT_max) of these species differed between T_a, habitat and species. Fish showed a species‐specific response to temperature increase, regardless of their habitat even under similar abiotic conditions. However, at the heat‐wave simulation, the demersal fish presented a greater thermal plasticity in relation to the pelagic fish. Despite the higher thermal tolerance when exposed to heat‐wave simulation, all fish species displayed a lower thermal edge safety that is markedly close to their maximum thermal limits.     

Effect of Duration of Exposure to Fluoride and Type of Diet on Lipid Parameters and De Novo Lipogenesis

Biological Trace Element Research - The effect of duration of chronic treatment with fluoride (F, 50 mg/L as NaF) on the lipid profile, lipid droplets and triglycerides (TG) in liver was...     

Effects of Aerobic Exercise Training on Cardiac Renin-Angiotensin System in an Obese Zucker Rat Strain

Objective

Obesity and renin angiotensin system (RAS) hyperactivity are profoundly involved in cardiovascular diseases, however aerobic exercise training (EXT) can prevent obesity and cardiac RAS activation. The study hypothesis was to investigate whether obesity and its association with EXT alter the systemic and cardiac RAS components in an obese Zucker rat strain.

Methods

The rats were divided into the following groups: Lean Zucker rats (LZR); lean Zucker rats plus EXT (LZR+EXT); obese Zucker rats (OZR) and obese Zucker rats plus EXT (OZR+EXT). EXT consisted of 10 weeks of 60-min swimming sessions, 5 days/week. At the end of the training protocol heart rate (HR), systolic blood pressure (SBP), cardiac hypertrophy (CH) and function, local and systemic components of RAS were evaluated. Also, systemic glucose, triglycerides, total cholesterol and its LDL and HDL fractions were measured.

Results

The resting HR decreased (∼12%) for both LZR+EXT and OZR+EXT. However, only the LZR+EXT reached significance (p<0.05), while a tendency was found for OZR versus OZR+EXT (p = 0.07). In addition, exercise reduced (57%) triglycerides and (61%) LDL in the OZR+EXT. The systemic angiotensin I-converting enzyme (ACE) activity did not differ regardless of obesity and EXT, however, the OZR and OZR+EXT showed (66%) and (42%), respectively, less angiotensin II (Ang II) plasma concentration when compared with LZR. Furthermore, the results showed that EXT in the OZR prevented increase in CH, cardiac ACE activity, Ang II and AT2 receptor caused by obesity. In addition, exercise augmented cardiac ACE2 in both training groups.

Conclusion

Despite the unchanged ACE and lower systemic Ang II levels in obesity, the cardiac RAS was increased in OZR and EXT in obese Zucker rats reduced some of the cardiac RAS components and prevented obesity-related CH. These results show that EXT prevented the heart RAS hyperactivity and cardiac maladaptive morphological alterations in obese Zucker rats.     

Oxidative Stress and Modification of Renal Vascular Permeability Are Associated with Acute Kidney Injury during P. berghei ANKA Infection

Malaria associated-acute kidney injury (AKI) is associated with 45% of mortality in adult patients hospitalized with severe form of the disease. However, the causes that lead to a framework of malaria-associated AKI are still poorly characterized. Some clinical studies speculate that oxidative stress products, a characteristic of Plasmodium infection, as well as proinflammatory response induced by the parasite are involved in its pathophysiology. Therefore, we aimed to investigate the development of malaria-associated AKI during infection by P. berghei ANKA, with special attention to the role played by the inflammatory response and the involvement of oxidative stress. For that, we took advantage of an experimental model of severe malaria that showed significant changes in the renal pathophysiology to investigate the role of malaria infection in the renal microvascular permeability and tissue injury. Therefore, BALB/c mice were infected with P. berghei ANKA. To assess renal function, creatinine, blood urea nitrogen, and ratio of proteinuria and creatininuria were evaluated. The products of oxidative stress, as well as cytokine profile were quantified in plasma and renal tissue. The change of renal microvascular permeability, tissue hypoxia and cellular apoptosis were also evaluated. Parasite infection resulted in renal dysfunction. Furthermore, we observed increased expression of adhesion molecule, proinflammatory cytokines and products of oxidative stress, associated with a decrease mRNA expression of HO-1 in kidney tissue of infected mice. The measurement of lipoprotein oxidizability also showed a significant increase in plasma of infected animals. Together, our findings support the idea that products of oxidative stress, as well as the immune response against the parasite are crucial to changes in kidney architecture and microvascular endothelial permeability of BALB/c mice infected with P. berghei ANKA.     

Tree Species Effect on Litter Decomposition and Nutrient Release in Mediterranean Oak Forests Changes Over Time

Tree species can affect the decomposition process through the quality of their leaf fall and through the species-specific conditions that they generate in their environment. We compared the relative importance of these effects in a 2-year experiment. Litterbags containing leaf litter of the winter-deciduous Quercus canariensis, the evergreen Q. suber and mixed litter were incubated beneath distinct plant covers. We measured litter carbon loss, 9 macro- and micronutrients and 18 soil chemical, physical and biological parameters of the incubation environment. Tree species affected decay dynamics through their litter quality and, to a lesser extent, through the induced environmental conditions. The deciduous litter showed a faster initial decomposition but left a larger fraction of slow decomposable biomass compared with the perennial litter; in contrast the deciduous environment impeded early decomposition while promoting further carbon loss in the latter decay stages. The interaction of these effects led to a negative litter–environment interaction contradicting the home-field advantage hypothesis. Leaf litter N, Ca and Mn as well as soil N, P and soil moisture were the best predictors for decomposition rates. Litter N and Ca exerted counteractive effects in early versus late decay stages; Mn was the best predictor for the decomposition limit value, that is, the fraction of slowly decomposable biomass at the later stage of decomposition; P and soil moisture showed a constant and positive relation with carbon loss. The deciduous oak litter had a higher initial nutrient content and released its nutrients faster and in a higher proportion than the perennial oak litter, significantly increasing soil fertility beneath its canopy. Our findings provide further insights into the factors that control the early and late stages of the decomposition process and reveal potential mechanisms underlying tree species influence on litter decay rate, carbon accumulation and nutrient cycling.