Prognostic Value of NT-proBNP versus Killip Classification in Patients with Acute Coronary Syndromes.

BACKGROUND: Plasma levels of brain natriuretic peptides have better diagnostic accuracy compared to clinical-radiologic judgment for acute heart failure. In acute coronary syndromes (ACS), the prognostic value of acute heart failure is incorporated into predictive models through Killip classification. It is not established whether NT-proBNP could increment prognostic prediction. OBJECTIVE: To evaluate whether NT-proBNP, as a measure of left ventricular dysfunction, improves the in-hospital prognostic value of the GRACE score in ACS. METHODS: Patients admitted due to acute chest pain, with electrocardiogram and/or troponin criteria for ACS were included in the study. The plasma level of NT-proBNP was measured at hospital admission and the primary endpoint was defined as cardiovascular death during hospitalization. P-value < 0.05 was considered as significant. RESULTS: Among 352 patients studied, cardiovascular mortality was 4.8%. The predictive value of NT-proBNP for cardiovascular death was shown by a C-statistic of 0.78 (95% CI = 0.65-0.90). After adjustment for the GRACE model subtracted by Killip variable, NT-proBNP remained independently associated with cardiovascular death (p = 0.015). However, discrimination by the GRACE-BNP logistic model (C-statistics = 0.83; 95%CI = 0.69-0.97) was not superior to the traditional GRACE Score with Killip (C-statistic = 0.82; 95%CI = 0.68-0.97). The GRACE-BNP model did not provide improvement in the classification of patients to high risk by the GRACE Score (net reclassification index = - 0.15; p = 0.14). CONCLUSION: Despite the statistical association with cardiovascular death, there was no evidence that NT-proBNP increments the prognostic value of GRACE score in ACS.

Cyclic fatigue resistance of three rotary file systems in a dynamic model after immersion in sodium hypochlorite.

To evaluate the effect of immersion in 3% sodium hypochlorite solution in the resistance to cyclic fatigue of three nickel-titanium (NiTi) rotary file systems, ProTaper Next (PTN), Hyflex CM (CM), and Hyflex EDM (EDM), in a mechanical model featuring axial movement. Ninety instruments of three different NiTi rotary file systems, PTN (size 25, 0.06 taper), CM (25, 0.06), and EDM (25/~, variable taper), were randomly divided according to a 3 × 3 factorial design and tested under dynamic immersion in a 3% NaOCl solution (1 or 5 min) or without immersion, making a total of 9 groups (n = 10). Files were tested in an artificial root canal with 45° angle and 5 mm radius apical curvature being submitted to back-and-forth movements until fracture. Statistical analysis was performed using two-way factorial ANOVA with Bonferroni post-hoc tests, at a significance level of 5%. Instruments were evaluated for reliability using a Weilbull approach. Regardless of the immersion treatment, PTN had on average 1200 ± 178 cycles to fracture, CM had 1949 ± 362, and EDM had 5573 ± 853, which was a significantly different (P < 0.01). The NaOCl immersion promoted a significant reduction in the mean number of cycles to fracture (P = 0.01), and was reflected in a significant reduction of the characteristic life of the instruments of the CM end EDM groups. Within this study conditions, EDM instruments performed better to cyclic fatigue followed by CM and then PTN. Immersion in NaOCl decreased the resistance to cyclic fatigue of all tested instruments, but affected more those manufactured from CM wire.

Inconsistency prevents the valuable synergism of explanatory and pragmatic trails.

OBJECTIVE: To assess review articles on pragmatic trials in order to describe how authors define the aim of this type of study, how comprehensive methodological topics are covered, and which topics are most valued by authors. METHODS: Review articles were selected from Medline Database, based on the expression "pragmatic trial" in the titles. Five trained medical students evaluated the articles, based on a list of 15 self-explanatory methodological topics. Each article was evaluated regarding topics covered. Baseline statements on the aim of pragmatic trials were derived. RESULTS: Among 22 articles identified, there was general agreement that the aim of a pragmatic trial is to evaluate if the intervention works under real-world conditions. The mean number of methodological topics addressed by each article was 7.6 ± 3.1. Only one article covered all 15 topics, three articles (14%) responded to at least 75% of topics and 13 articles (59%) mentioned at least 50% of the topics. The relative frequency each of the 15 topics was cited by articles had a mean of 50% ± 25%. No topic was addressed by all articles, only three (20%) were addressed by more than 75% of articles. CONCLUSIONS: There is agreement on the different aims of explanatory and pragmatic trials. But there is a large variation on methodological topics used to define a pragmatic trial, which led to inconsistency in defining the typical methodology of a pragmatic trial.

MORTALITY OF URGENCY VERSUS ELECTIVE VIDEOLAPAROSCOPIC CHOLECYSTECTOMY FOR ACUTE CHOLECYSTITIS.

Background: Surgical approach is still controversial in patients with acute cholecystitis: to treat clinically the inflammatory process and operate electively later or to operate immediately on an emergency basis? Aim: To test the hypothesis that urgent laparoscopic cholecystectomy in acute cholecystitis has a higher mortality than elective laparoscopic cholecystectomy. Methods: From the data available in Datasus, mortality was compared between patients undergoing elective laparoscopic cholecystectomy for cholelithiasis and in urgency. Calculations were made of the relative reduction in risk of death, absolute reduction of risk of death and number needed to treat. Results: From 2009 to 2014 in Brazil, there were 250.439 laparoscopic cholecystectomy and 74.6% were electives. Mortality in the emergency group was 4.8 times higher compared to the elective group (0.0023% vs. 0.00048%). Despite the relative reduction in risk of death (RRR) was 83%, in the calculation of absolute risk was found 0.0018 and number needed to treat of 55,555. Conclusions: Despite the relative risk reduction for mortality was high comparing elective vs. urgent basis, the absolute risk reduction was minimal, since this outcome is very low in both groups, suggesting that mortality should not have much influence on surgical decision.

Racional: Continua controversa a conduta nos pacientes com colecistite aguda: compensar o processo inflamatório e operar eletivamente ou operar imediatamente em caráter de urgência? Objetivo: Testar a hipótese de que a colecistectomia videolaparoscópica de urgência por colecistite aguda apresenta maior mortalidade que a colecistectomia videolaparoscópica eletiva. Métodos: A partir dos dados disponíveis no Datasus, foi comparada a mortalidade entre os pacientes submetidos à colecistectomia videolaparoscópica eletiva por colelitíase e a de urgência. Foram realizados cálculos da redução relativa de risco de morte, redução absoluta do risco de morte e número necessário para tartar. Resultados: De 2009 a 2014 no Brasil, foram realizadas 250.439 colecistectomias videolaparoscópicas sendo 74,6% eletivas. A mortalidade no grupo de emergência foi 4,8 vezes mais elevada em comparação com o grupo eletivo (0,0023% vs. 0,00048%). Apesar da redução relativa do risco de morte (RRR) ser de 83%, no cálculo do risco absoluto encontrou-se 0,0018 e número necessário para tratar de 55.555. Conclusões: Apesar da redução relativa de risco para mortalidade ser alta comparando o caráter eletivo vs. urgência, a redução de risco absoluto é mínima, já que esse desfecho é muito baixo nos dois grupos, sugerindo que a mortalidade não deve ter muita influência na tomada de decisão cirúrgica.

Mortality of urgency versus elective videolaparoscopic cholecystectomy for acute cholecystitis / Mortalidade da colecistectomia videolaparoscópica de urgência versus operação eletiva para colecistite aguda

ABSTRACT Background: Surgical approach is still controversial in patients with acute cholecystitis: to treat clinically the inflammatory process and operate electively later or to operate immediately on an emergency basis? Aim: To test the hypothesis that urgent laparoscopic cholecystectomy in acute cholecystitis has a higher mortality than elective laparoscopic cholecystectomy. Methods: From the data available in Datasus, mortality was compared between patients undergoing elective laparoscopic cholecystectomy for cholelithiasis and in urgency. Calculations were made of the relative reduction in risk of death, absolute reduction of risk of death and number needed to treat. Results: From 2009 to 2014 in Brazil, there were 250.439 laparoscopic cholecystectomy and 74.6% were electives. Mortality in the emergency group was 4.8 times higher compared to the elective group (0.0023% vs. 0.00048%). Despite the relative reduction in risk of death (RRR) was 83%, in the calculation of absolute risk was found 0.0018 and number needed to treat of 55,555. Conclusions: Despite the relative risk reduction for mortality was high comparing elective vs. urgent basis, the absolute risk reduction was minimal, since this outcome is very low in both groups, suggesting that mortality should not have much influence on surgical decision.

RESUMO Racional: Continua controversa a conduta nos pacientes com colecistite aguda: compensar o processo inflamatório e operar eletivamente ou operar imediatamente em caráter de urgência? Objetivo: Testar a hipótese de que a colecistectomia videolaparoscópica de urgência por colecistite aguda apresenta maior mortalidade que a colecistectomia videolaparoscópica eletiva Métodos: A partir dos dados disponíveis no Datasus, foi comparada a mortalidade entre os pacientes submetidos à colecistectomia videolaparoscópica eletiva por colelitíase e a de urgência. Foram realizados cálculos da redução relativa de risco de morte, redução absoluta do risco de morte e número necessário para tratar . Resultados: De 2009 a 2014 no Brasil, foram realizadas 250.439 colecistectomias videolaparoscópicas sendo 74,6% eletivas. A mortalidade no grupo de emergência foi 4,8 vezes mais elevada em comparação com o grupo eletivo (0,0023% vs. 0,00048%). Apesar da redução relativa do risco de morte (RRR) ser de 83%, no cálculo do risco absoluto encontrou-se 0,0018 e número necessário para tratar de 55.555. Conclusões: Apesar da redução relativa de risco para mortalidade ser alta comparando o caráter eletivo vs. urgência, a redução de risco absoluto é mínima, já que esse desfecho é muito baixo nos dois grupos, sugerindo que a mortalidade não deve ter muita influência na tomada de decisão cirúrgica.

Genetic characterization of the role of the Cip/Kip family of proteins as cyclin-dependent kinase inhibitors and assembly factors.

The Cip/Kip family, namely, p21(Cip1), p27(Kip1), and p57(Kip2), are stoichiometric cyclin-dependent kinase inhibitors (CKIs). Paradoxically, they have been proposed to also act as positive regulators of Cdk4/6-cyclin D by stabilizing these heterodimers. Loss of p21(Cip1) and p27(Kip1) reduces Cdk4/6-cyclin D complexes, although with limited phenotypic consequences compared to the embryonic lethality of Cdk4/6 or triple cyclin D deficiency. This milder phenotype was attributed to Cdk2 compensatory mechanisms. To address this controversy using a genetic approach, we generated Cdk2(-/-) p21(-/-) p27(-/-) mice. Triple-knockout mouse embryonic fibroblasts (MEFs) displayed minimal levels of D-type cyclins and Cdk4/6-cyclin D complexes. p57(Kip2) downregulation in the absence of p21(Cip1) and p27(Kip1) aggravated this phenotype, yet MEFs lacking all Cip/Kip proteins exhibited increased retinoblastoma phosphorylation, together with enhanced proliferation and transformation capacity. In vivo, Cdk2 ablation induced partial perinatal lethality in p21(-/-) p27(-/-) mice, suggesting partial Cdk2-dependent compensation. However, Cdk2(-/-) p21(-/-) p27(-/-) survivors displayed all phenotypes described for p27(-/-) mice, including organomegalia and pituitary tumors. Thus, Cip/Kip deficiency does not impair interphasic Cdk activity even in the absence of Cdk2, suggesting that their Cdk-cyclin assembly function is dispensable for homeostatic control in most cell types.

A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease, characterized by motor neuron (MN) death, for which there are no truly effective treatments. Here, we describe a new small molecule survival screen carried out using MNs from both wild-type and mutant SOD1 mouse embryonic stem cells. Among the hits we found, kenpaullone had a particularly impressive ability to prolong the healthy survival of both types of MNs that can be attributed to its dual inhibition of GSK-3 and HGK kinases. Furthermore, kenpaullone also strongly improved the survival of human MNs derived from ALS-patient-induced pluripotent stem cells and was more active than either of two compounds, olesoxime and dexpramipexole, that recently failed in ALS clinical trials. Our studies demonstrate the value of a stem cell approach to drug discovery and point to a new paradigm for identification and preclinical testing of future ALS therapeutics.

A screen for regulators of survival of motor neuron protein levels.

The motor neuron disease spinal muscular atrophy (SMA) results from mutations that lead to low levels of the ubiquitously expressed protein survival of motor neuron (SMN). An ever-increasing collection of data suggests that therapeutics that elevate SMN may be effective in treating SMA. We executed an image-based screen of annotated chemical libraries and discovered several classes of compounds that were able to increase cellular SMN. Among the most important was the RTK-PI3K-AKT-GSK-3 signaling cascade. Chemical inhibitors of glycogen synthase kinase 3 (GSK-3) and short hairpin RNAs (shRNAs) directed against this target elevated SMN levels primarily by stabilizing the protein. It was particularly notable that GSK-3 chemical inhibitors were also effective in motor neurons, not only in elevating SMN levels, but also in blocking the death that was produced when SMN was acutely reduced by an SMN-specific shRNA. Thus, we have established a screen capable of detecting drug-like compounds that correct the main phenotypic change underlying SMA.

Trauma contuso de artéria carótida interna após acidente automobilístico: apresentação de um caso / Blunt internal carotid artery injury after a motor vehicle crash: presentation of a case

Este estudo relata o caso de uma paciente vítima de acidente automobilístico, que desenvolveu quadro de hemiplegia poucas horas depois do trauma. Na propedêutica diagnosticou-se acidente vascular cerebral isquêmico (AVCi) secundário à trombose da artéria carótida interna direita. O objetivo é alertar para o trauma contuso vascular como diagnóstico diferencial de injúrias neurológicas.

This work relates a occurrence of a patient victim of a motor vehicle crash that developed signs of unilateral paralysis few hours after the trauma. At investigation a diagnosis of ischemic stroke due a right carotid artery thrombosis was made. The objective of this article is to alert about the blunt vascular trauma as a differential diagnostic of neurologic injuries.

Overall Cdk activity modulates the DNA damage response in mammalian cells.

In response to DNA damage, cells activate a phosphorylation-based signaling cascade known as the DNA damage response (DDR). One of the main outcomes of DDR activation is inhibition of cyclin-dependent kinase (Cdk) activity to restrain cell cycle progression until lesions are healed. Recent studies have revealed a reverse connection by which Cdk activity modulates processing of DNA break ends and DDR activation. However, the specific contribution of individual Cdks to this process remains poorly understood. To address this issue, we have examined the DDR in murine cells carrying a defined set of Cdks. Our results reveal that genome maintenance programs of postreplicative cells, including DDR, are regulated by the overall level of Cdk activity and not by specific Cdks.

Cdk1 is sufficient to drive the mammalian cell cycle.

Unicellular organisms such as yeasts require a single cyclin-dependent kinase, Cdk1, to drive cell division. In contrast, mammalian cells are thought to require the sequential activation of at least four different cyclin-dependent kinases, Cdk2, Cdk3, Cdk4 and Cdk6, to drive cells through interphase, as well as Cdk1 to proceed through mitosis. This model has been challenged by recent genetic evidence that mice survive in the absence of individual interphase Cdks. Moreover, most mouse cell types proliferate in the absence of two or even three interphase Cdks. Similar results have been obtained on ablation of some of the activating subunits of Cdks, such as the D-type and E-type cyclins. Here we show that mouse embryos lacking all interphase Cdks (Cdk2, Cdk3, Cdk4 and Cdk6) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins, resulting in the phosphorylation of the retinoblastoma protein pRb and the expression of genes that are regulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryos proliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins. However, they become immortal on continuous passage. We also report that embryos fail to develop to the morula and blastocyst stages in the absence of Cdk1. These results indicate that Cdk1 is the only essential cell cycle Cdk. Moreover, they show that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division.

Mice thrive without Cdk4 and Cdk2.

Mammalian cell division is thought to be driven by sequential activation of several Cyclin-dependent kinases (Cdk), mainly Cdk4, Cdk6, Cdk2 and Cdk1. Since mice lacking Cdk4, Cdk6 or Cdk2 are viable, it has been proposed that they play compensatory roles. We report here that mice lacking Cdk4 and Cdk2 complete embryonic development to die shortly thereafter presumably due to heart failure. However, conditional ablation of Cdk2 in adult mice lacking Cdk4 does not result in obvious abnormalities. Moreover, these double mutant mice recover normally after partial hepatectomy. In culture, Cdk4(-/-);Cdk2(-/-) embryonic fibroblasts become immortal, display robust pRb phosphorylation and have normal S phase kinetics. These observations indicate that Cdk4 and Cdk2 are dispensable for the mammalian cell cycle and for adult homeostasis.