Fosfatriclaben: Effective dose determination and comparative efficacy assessment with closantel, triclabendazole+ivermectin, triclabendazole+albendazole in artificially infected cattle.

Two controlled efficacy studies were conducted to determine the effective dose of fosfatriclaben (FTCB) and compare its fasciolicidal efficacy with that of three commercial products against eggs and adult stages of Fasciola hepatica in artificially infected cattle. In study 1, 20 trematode-free Holstein Friesian steers were infected on day 0 with 500 F. hepatica metacercariae. Ten weeks after infection and the steers were confirmed to be positive for trematode eggs through a modified sedimentation method. On day 75, they were divided into five groups of four animals each for treatment. Group 1 (G1) served as the untreated control; G2, G3, and G4 received FTCB at 4, 6, and 8 mg/kg/intramuscularly (IM), respectively. G5 received a combined treatment of triclabendazole (TCBZ) (12 mg/kg IM + ivermectin (0.2 mg/kg IM). Individual faecal analyses were performed on days -8, 0, 70, 75, and 105 to evaluate the reduction in trematode eggs. Four weeks after treatment, the steers were humanely slaughtered to harvest the livers and remove the parasites present in the bile ducts. Efficacy was evaluated by the reduction in fecal egg counts or in number of adult parasites, compared to the untreated control. The effective FTCB dose was 6 mg/kg. Once the effective dose was determined, study 2 was conducted on another 20 steers infected with 500 F. hepatica metacercariae, to compare the effectiveness of FTCB with three commercials fasciolicides. All procedures were performed as described in study 1, and treatments were as follows: Group 1 (G1), closantel (5 mg/kg subcutaneously (SC)); G2, TCBZ (12 mg/kg IM) + ivermectin (0.2 mg/kg IM); G3, FTCB (6 mg/kg IM); G4, triclabendazole (12 mg/kg) + albendazole (5 mg/kg/PO (orally); and G5 served as an untreated control. The results indicated that all tested compounds were highly effective in the reduction of faecal egg excretion (99.7-100%) and adult parasites (98.9-100%), except closantel, which exhibited low efficacy (74.4%) when tested against adult trematodes. We concluded that the effective dose of FTCB for cattle was 6 mg/kg IM, which is half the recommended clinical dose of the commercial combination of TCBZ and ivermectin. The fasciolicidal efficacy of FTCB was like the other three flukicides in reducing adult F. hepatica and Fasciola eggs; however, closantel was not sufficiently efficient against adult flukes.

Action observation for upper limb rehabilitation after stroke.

BACKGROUND: Action observation (AO) is a physical rehabilitation approach that facilitates the occurrence of neural plasticity through the activation of the mirror-neural system, promoting motor recovery in people with stroke. OBJECTIVES: To assess whether AO enhances upper limb motor function in people with stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 18 May 2021), the Cochrane Central Register of Controlled Trials (18 May 2021), MEDLINE (1946 to 18 May 2021), Embase (1974 to 18 May 2021), and five additional databases. We also searched trial registries and reference lists. SELECTION CRITERIA: Randomized controlled trials (RCTs) of AO alone or associated with physical practice in adults after stroke. The primary outcome was upper limb (arm and hand) motor function. Secondary outcomes included dependence on activities of daily living (ADL), motor performance, cortical activation, quality of life, and adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials according to the predefined inclusion criteria, extracted data, assessed risk of bias using RoB 1, and applied the GRADE approach to assess the certainty of the evidence. The reviews authors contacted trial authors for clarification and missing information. MAIN RESULTS: We included 16 trials involving 574 individuals. Most trials provided AO followed by the practice of motor actions. Training varied between 1 day and 8 weeks of therapy, 10 to 90 minutes per session. The time of AO ranged from 1 minute to 10 minutes for each motor action, task or movement observed. The total number of motor actions ranged from 1 to 3. Control comparisons included sham observation, physical therapy, and functional activity practice. PRIMARY OUTCOMES: AO improved arm function (standardized mean difference (SMD) 0.39, 95% confidence interval (CI) 0.17 to 0.61; 11 trials, 373 participants; low-certainty evidence); and improved hand function (mean difference (MD) 2.76, 95% CI 1.04 to 4.49; 5 trials, 178 participants; low-certainty evidence). SECONDARY OUTCOMES: AO did not improve ADL performance (SMD 0.37, 95% CI -0.34 to 1.08; 7 trials, 302 participants; very low-certainty evidence), or quality of life (MD 5.52, 95% CI -30.74 to 41.78; 2 trials, 30 participants; very low-certainty evidence). We were unable to pool the other secondary outcomes (motor performance and cortical activation). Only two trials reported adverse events without significant adverse effects. AUTHORS' CONCLUSIONS: The effects of AO are small for arm function compared to any control group; for hand function the effects are large, but not clinically significant. For both, the certainty of evidence is low. There is no evidence of benefit or detriment from AO on ADL and quality of life of people with stroke; however, the certainty of evidence is very low. As such, our confidence in the effect estimate is limited because it will likely change with future research.

Field study on the determination of the effective dose of injectable fosfatriclaben prodrug in sheep naturally infected with Fasciola hepatica.

The aim of the present study was to determine the effective dose of fosfatriclaben through a field study in sheep naturally infected with F. hepatica. Thirty crossbred sheep positive for fluke eggs were selected for inclusion in the trial. On day 0, 5 groups of 6 animals each were formed for treatments: group 1 (G1), G2, and G3 received fosfatriclaben at 4, 6, and 8 mg/kg/IM, respectively. G4 received triclabendazole at 10 mg/kg/PO, and G5 was the untreated control group. Fecal samples of the sheep were analyzed to count the number of fluke eggs to evaluate the percentage of egg reduction. Twenty-one days after treatment, all sheep were humanely euthanized to extract the flukes from the bile ducts. They were counted to assess the percentage of fluke reduction. Fosfatriclaben reduced fluke eggs by 99.6, 99.6, and 100% and flukes by 94.3, 100, and 100%, respectively. Triclabendazole reduced fluke eggs by 95.2% and flukes by 100%. The fosfatriclaben injectable prodrug showed a high fasciolicidal efficacy similar to triclabendazole, with advantages over its predecessor, since only half the dose as compared to triclabendazole was required to remove eggs and flukes in the sheep that were studied.

Predictive factors of functional independence in basic activities of daily living during hospitalization and after discharge of stroke patients.

Objective: The aim of this study was to identify the predictive factors of functional independence in the basic activities of daily living during hospitalization, on the 10th and 28th day after stroke.Methods: A total of 433 patients (204 men and 229 women) took part. Functional independence data were collected using the Step 1 from an instrument called Stepwise. Analysis was conducted by logistic regression.Results: Due to the OR values below 1.0 we can verify that the age of 59 years or less and the presence of physiotherapy in the hospital were protective factors of functional independence. Other predictive factors were the number of stroke risk factors (bathing: OR = 0.4; p = .005, transfer: OR = 0.487; p = .025), the amount of medication used before stroke (bathing: OR = 1.7; p = .013), sex (grooming: OR = 1.6; p = .026); type of stroke (continence: OR = 2.2; p = .003-10th day; OR = 1.9; p = .013-28th day), previous strokes (eating: OR = 0.5; p = .036).Conclusions: According to the results, the risk of impaired functional independence decreased in bathing and eating and increased for dressing, grooming and transfer during clinical recovery suggesting the need for greater therapeutic intervention in different basic activities of daily living.

Action observation for upper limb rehabilitation after stroke.

BACKGROUND: Action observation (AO) is a physical rehabilitation approach that facilitates the occurrence of neural plasticity through the activation of the mirror-neural system, promoting motor recovery in people with stroke. OBJECTIVES: To assess whether action observation enhances motor function and upper limb motor performance and cortical activation in people with stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 4 September 2017), the Central Register of Controlled Trials (24 October 2017), MEDLINE (1946 to 24 October 2017), Embase (1974 to 24 October 2017) and five additional databases. We also searched trial registries and reference lists. SELECTION CRITERIA: Randomized controlled trials (RCTs) of AO, alone or associated with physical practice in adults after stroke. The primary outcome was upper limb motor function. Secondary outcomes included dependence on activities of daily living (ADL), motor performance, cortical activation, quality of life, and adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials according to the pre-defined inclusion criteria, extracted data, assessed risk of bias, and applied the GRADE approach to assess the quality of the evidence. The reviews authors contacted trial authors for clarification and missing information. MAIN RESULTS: We included 12 trials involving 478 individuals. A number of trials showed a high risk of bias and others an unclear risk of bias due to poor reporting. The quality of the evidence was 'low' for most of the outcomes and 'moderate' for hand function, according to the GRADE system. In most of the studies, AO was followed by some form of physical activity. PRIMARY OUTCOME: the impact of AO on arm function showed a small significant effect (standardized mean difference (SMD) 0.36, 95% CI 0.13 to 0.60; 8 studies; 314 participants; low-quality evidence); and a large significant effect (mean difference (MD) 2.90, 95% CI 1.13 to 4.66; 3 studies; 132 participants; moderate-quality evidence) on hand function. SECONDARY OUTCOMES: there was a large significant effect for ADL outcome (SMD 0.86, 95% CI 0.11 to 1.61; 4 studies, 226 participants; low-quality evidence). We were unable to pool other secondary outcomes to extract the evidence. Only two studies reported adverse effects without significant adverse AO events. AUTHORS' CONCLUSIONS: We found evidence that AO is beneficial in improving upper limb motor function and dependence in activities of daily living (ADL) in people with stroke, when compared with any control group; however, we considered the quality of the evidence to be low. We considered the effect of AO on hand function to be large, but it does not appear to be clinically relevant, although we considered the quality of the evidence as moderate. As such, our confidence in the effect estimate is limited because it will likely change with future research.

Rapamycin requires AMPK activity and p27 expression for promoting autophagy-dependent Tsc2-null cell survival.

Tuberous sclerosis complex (TSC) disease results from inactivation of the TSC1 or TSC2 gene, and is characterized by benign tumors in several organs. Because TSC tumorigenesis correlates with hyperactivation of mTORC1, current therapies focus on mTORC1 inhibition with rapamycin or its analogs. Rapamycin-induced tumor shrinkage has been reported, but tumor recurrence occurs on withdrawal from rapamycin. Autophagy has been associated with development of TSC tumors and with tumor cell survival during rapamycin treatment. mTORC1 and AMPK directly inhibit and activate autophagy, respectively. AMPK is hyperactivated in TSC cells and tumors, and drives cytoplasmic sequestration of the cell-cycle inhibitor p27KIP (p27). Whether AMPK and p27 are involved in rapamycin-induced autophagy and survival of TSC cells remain unexplored. Here, we show that inhibition of AMPK by compound C or by shRNA-mediated depletion of LKB1 reduces activation of autophagy by rapamycin in Tsc2-null cells. Similarly, shRNA-mediated depletion of p27 inhibited rapamycin-induced autophagy. In support of p27 lying downstream of AMPK on the activation of autophagy in Tsc2-null cells, a p27 mutant that preferentially localizes in the cytosol recovered the effect of rapamycin on autophagy in both p27- and LKB1-depleted cells, but a nuclear p27 mutant was inactive. Finally, we show that p27-dependent activation of autophagy is involved in Tsc2-null cell survival under rapamycin treatment. These results indicate that an AMPK/p27 axis is promoting a survival mechanism that could explain in part the relapse of TSC tumors treated with rapamycin, exposing new avenues for designing more efficient treatments for TSC patients.

Rheb signaling and tumorigenesis: mTORC1 and new horizons.

Rheb is a conserved small GTPase that belongs to the Ras superfamily, and is mainly involved in activation of cell growth through stimulation of mTORC1 activity. Because deregulation of the Rheb/mTORC1 signaling is associated with proliferative disorders and cancer, inhibition of mTORC1 has been therapeutically approached. Although this therapy has proven antitumor activity, its efficacy is not as expected. Here, we will review the main work on the identification of the role of Rheb in cell growth, and on the relevance of Rheb in proliferative disorders, including cancer. We will also review the Rheb functions that could explain tumor resistance to therapies with mTORC1 inhibitors, and will mainly focus our discussion on mTORC1-independent Rheb functions that could also be implicated in cancer cell survival and tumorigenesis. The current progress on the understanding of the noncanonical Rheb functions prompts future studies to establish their relevance in cancer and in the context of current cancer therapies.

Rheb promotes cancer cell survival through p27Kip1-dependent activation of autophagy.

We previously found that the small GTPase Rheb regulates the cell-cycle inhibitor p27KIP1 (p27) in colon cancer cells by a mTORC1-independent mechanism. However, the biological function of the Rheb/p27 axis in cancer cells remains unknown. Here, we show that siRNA-mediated depletion of Rheb decreases survival of human colon cancer cells under serum deprivation. As autophagy can support cell survival, we analyzed the effect of Rheb on this process by detecting the modification of the autophagy marker protein LC3 by western blot and imunofluorescence. We found that Rheb promotes autophagy in several human cancer cell lines under serum deprivation. Accordingly, blocking autophagy inhibited the pro-survival effect of Rheb in colon cancer cells. We then analyzed whether p27 was involved in the biological effect of Rheb. Depletion of p27 inhibited colon cancer cell survival, and Rheb induction of autophagy. These results suggest that p27 has an essential role in the effect of Rheb in response to serum deprivation. In addition, we demonstrated that the role of p27 in autophagy stands on the N-terminal portion of the protein, where the CDK-inhibitory domain is located. Our results indicate that a Rheb/p27 axis accounts for the activation of autophagy that supports cancer cell survival. Our work therefore highlights a biological function of Rheb and prompts the need for future studies to address whether the mTORC1-independent Rheb/p27 axis could contribute to tumorigenesis and/or resistance to mTOR inhibitors.

Maximal respiratory pressures of healthy children: comparison between obtained and predicted values.

PURPOSE: To compare maximal inspiratory and expiratory pressures (PImax and PEmax, respectively) obtained in Brazilian children who are healthy with reference and predicted values from previous studies. METHODS: Respiratory muscle strength of 144 children (63 boys), aged 7 to 11 years, was assessed. A digital manovacuometer was used to measure PImax and PEmax from residual volume and total lung capacity, respectively. Children were assessed in the sitting position while wearing a nose clip. RESULTS: Mean values of PImax for boys and girls were 81.6 ± 20.2 and 66.1 ± 19.5 cmH2O, respectively. Mean values of PEmax in boys and girls were 95.6 ± 21.1 and 78.9 ± 19.7 cmH2O, respectively. CONCLUSIONS: Published reference values demonstrated a wide diversity across age groups studied, and published equations were not successful in predicting maximal respiratory pressures; thus, the assessment of respiratory muscle strength of children should consider the minimization of ethnic and methodological differences.

Social rhythm and implications on functionality of patients after stroke.

The study aimed to assess the regularity, intensity, frequency, and period of activities comprising social rhythm and associate them with the functionality of stroke patients. The sample consisted of 73 patients (41 men and 32 women) with a mean age of 60 years (±10). Social rhythm was assessed by Social Rhythm Metric (SRM) and Activity Level Index (ALI). The functionality was evaluated using the International Classification of Functioning, Disability, and Health (ICF). Data were analyzed using Student's t-test, ANOVA, and Chi-square test. The mean SRM was 5.1 ± 0.9, and ALI was 58.3 ± 14.9. Notably, 40% of the patients exhibited both low regularity and low intensity of activities. Six SRM activities, performed with low frequency (going outside, starting work, exercising, snacking, watching other TV programs, and going home), exhibited a tendency to have periods that deviated from the expected 24-hour daily cycle. ICF domains most associated with SRM were: d2-General tasks and demands, d3-Communication, d4-Mobility, d5-Self care, d8-Major life areas, and d9-Community, social and civic life. The results indicated changes in social rhythm with implications for patient functionality. Screening for disruptions in social rhythm could be part of the functional assessment during the rehabilitation process for post-stroke patients.

Fosfatriclaben, a prodrug of triclabendazole: Preparation, stability, and fasciolicidal activity of three new intramuscular formulations.

In this study, we present the preparation, stability, and in vivo fasciolicidal activity of three new intramuscular formulations in sheep of a prodrug based on triclabendazole, named fosfatriclaben. The new formulations were ready-to-use aqueous solutions with volumes recommended for intramuscular administration in sheep. The use of poloxamers (P-407 and P-188) and polysorbates (PS-20 and PS-80) in the new formulations improved the aqueous solubility of fosfatriclaben by 8-fold at pH 7.4. High-performance liquid chromatography with UV detection was used to evaluate the stability of fosfatriclaben in the three formulations. High recovery (> 90%) of fosfatriclaben was found for all formulations after exposure at 57 ± 2 °C for 50 h. The three intramuscular formulations showed high fasciolicidal activity at a dose of 6 mg/kg, which was equivalent to the triclabendazole content. The fasciolicidal activity of fosfatriclaben was similar to commercial oral (Fasimec®) and intramuscular (Endovet®) triclabendazole formulations at a dose of 12 mg/kg. In the in vivo experiments, all formulations administered intramuscularly reduced egg excretion by 100%, and formulations F1, F2, and F3 presented fasciolicidal activities of 100%, 100%, and 99.6%, respectively.

Predictive factors of subjective sleep quality and insomnia complaint in patients with stroke: implications for clinical practice.

The complaints regarding sleep problems have not been well identified after a stroke. The aim of this study was to investigate the predictive factors of sleep quality and insomnia complaints in patients with stroke. A total of 70 subjects, 40 patients (57 ± 7 years) and 30 healthy controls (52 ± 6 years) assessed by the Pittsburgh Sleep Quality Index (PSQI) and the Sleep Habits Questionnaire took part in the study. The data were analyzed using the chi-square test, the Student's t-test and logistic regression analysis. On average, the patients showed poor sleep quality (patients: 6.3 ± 3.5; controls: 3.9 ± 2.2; p= 0.002) and insomnia complaint was the most prevalent (patients: 37.5%; controls: 6.7%; p= 0.007). The absence of insomnia complaint (OR= 0.120; 95%CI= 0.017-0.873; p= 0.036) and the decreased latency of sleep (OR= 0.120; 95%CI= 0.017-0.873; p= 0.036) were the protective factors of sleep quality. Female sex (OR= 11.098; 95%CI= 1.167-105.559; p= 0.036) and fragmented sleep (OR= 32.040; 95%CI= 3.236-317.261; p= 0.003) were the risk factors for insomnia complaint. We suggest that complaints of poor sleep quality and insomnia should be given priority assessment during clinical diagnosis of sleep disorders in stroke.

A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.

M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells.

Constitutive activation of M-Ras has previously been reported to cause morphologic and growth transformation of murine cells, suggesting that M-Ras plays a role in tumorigenesis. Cell transformation by M-Ras correlated with weak activation of the Raf/MEK/ERK pathway, although contributions from other downstream effectors were suggested. Recent studies indicate that signaling events distinct from the Raf/MEK/ERK cascade are critical for human tumorigenesis. However, it is unknown what signaling events M-Ras triggers in human cells. Using constitutively active M-Ras (Q71L) containing additional mutations within its effector-binding loop, we found that M-Ras induces MEK/ERK-dependent and -independent Elk1 activation as well as phosphatidylinositol 3 kinase (PI3K)/Akt and JNK/cJun activation in human MCF-7 breast cancer cells. Among several human cell lines examined, M-Ras-induced MEK/ERK-independent Elk1 activation was only detected in MCF-7 cells, and correlated with Rlf/M-Ras interaction and Ral/JNK activation. Supporting a role for M-Ras signaling in breast cancer, EGF activated M-Ras and promoted its interaction with endogenous Rlf. In addition, constitutive activation of M-Ras induced estrogen-independent growth of MCF-7 cells that was dependent on PI3K/Akt, MEK/ERK, and JNK activation. Thus, our studies demonstrate that M-Ras signaling activity differs between human cells, highlighting the importance of defining Ras protein signaling within each cell type, especially when designing treatments for Ras-induced cancer. These findings also demonstrate that M-Ras activity may be important for progression of EGFR-dependent tumors.

Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution.

Germ-line hypomorphism of the pleiotropic transcription factor Myc in mice, either through Myc gene haploinsufficiency or deletion of Myc enhancers, delays onset of various cancers while mice remain viable and exhibit only relatively mild pathologies. Using a genetically engineered mouse model in which Myc expression may be systemically and reversibly hypomorphed at will, we asked whether this resistance to tumour progression is also emplaced when Myc hypomorphism is acutely imposed in adult mice. Indeed, adult Myc hypomorphism profoundly blocked KRasG12D-driven lung and pancreatic cancers, arresting their evolution at the early transition from indolent pre-tumour to invasive cancer. We show that such arrest is due to the incapacity of hypomorphic levels of Myc to drive release of signals that instruct the microenvironmental remodelling necessary to support invasive cancer. The cancer protection afforded by long-term adult imposition of Myc hypomorphism is accompanied by only mild collateral side effects, principally in haematopoiesis, but even these are circumvented if Myc hypomorphism is imposed metronomically whereas potent cancer protection is retained.

Is motor learning of stroke patients in non-immersive virtual environment influenced by laterality of injury? A preliminary study.

BACKGROUND: Stroke is the leading cause of long-term disability in adults, causing residual sensorimotor deficits in many survivors. Patients may have different impairments according to laterality of injury, as well as different responses to some therapies. OBJECTIVE: This preliminary study sought to investigate motor learning in rehabilitation of stroke patients with non-immersive virtual environment by process (electroencephalography) and product (performance) measures in stroke patients with left and right cerebral hemispheres damage. METHODS: The study included 10 chronic stroke patients; 5 with left brain injury (LI), mean age 48.8 years (±4.76), and 5 with right brain injury (RI), mean age 52 years (±10.93). Patients were evaluated for electroencephalographic activity (alpha and beta frequencies) and performance (absolute error) in a darts game on XBOX Kinect (Microsoft®). Then they underwent a virtual darts game training task, 12 sessions for 4 weeks (acquisition stage). After training, they were revaluated (long-term retention). RESULTS: RI group increased alpha power and decreased beta in ipsilesional areas, increased activation on left hemisphere and decreased the absolute error of performance; LI group increased right hemisphere activation and did not decrease the absolute error. CONCLUSIONS: Patients with right brain injury reduce neural effort and errors after virtual darts training, which did not happen to patients with left brain injury. Therefore, the laterality of lesion should be considered in studies that use virtual reality for stroke rehabilitation.

Effectiveness of an experimental injectable prodrug formulation against Fasciola hepatica of different ages in experimentally infected sheep.

In this work, we present an evaluation of the fasciolicidal efficacy of a new injectable formulation of fosfatriclaben in comparison with the subcutaneous closantel and oral triclabendazole formulations currently used in veterinary practice as fasciolicides. The study was carried out in vivo on Fasciola hepatica at 2, 4, 6 and 8 weeks of age in experimentally infected sheep. To evaluate the formulation, the percent reduction of the parasite load was measured and the number of fluke eggs. Fosfatriclaben was used at 6 mg/kg/IM (dose equivalent to triclabendazole content), closantel at 5% at 10 mg/kg/SC, and triclabendazole at 10 mg/kg/PO; the control group received no treatment. Fosfatriclaben showed fasciolicidal efficacies of 95.5 %, 100 %, 100 % and 100 %, and triclabendazole showed similar efficacies of 97.4 %, 100 %, 100 % and 100 %, at the different treatment weeks (P > 0.05). Closantel showed limited efficacy against 2-, 4- and 6-week-old flukes but 100 % efficacy in adult flukes. All three evaluated formulations eliminated all 8-week-old F. hepatica trematode eggs. Although fosfatriclaben and triclabendazole showed similar fasciolicidal efficacy, the intramuscular administration of fosfatriclaben has several advantages over the oral administration of triclabendazole, such as ease of administration for veterinary use and a reduced risk of accidents for both the operator and the animals. In addition, the dose used in this injectable formulation is only 60 % of the oral dose, which reduces environmental contamination.

MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype.

The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of Myc in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells in vivo is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this Myc-driven PDAC switch is completely and immediately reversible: Myc deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible Myc switch. SIGNIFICANCE: We show that Myc activation in indolent Kras G12D-induced PanIN epithelium acts as an immediate pleiotropic switch, triggering tissue-specific signals that instruct all the diverse signature stromal features of spontaneous human PDAC. Subsequent Myc deactivation or inhibition immediately triggers a program that coordinately disassembles PDAC back to PanIN.See related commentary by English and Sears, p. 495.

Effects of exergames training on postural balance in patients who had a chronic stroke: study protocol for a randomised controlled trial.

INTRODUCTION: Exergames training, as an additional therapy to standard care, has been widely used for motor recovery after patients who had a stroke, and it is a valuable and positive tool in the rehabilitation of this population. This study describes a single-blind randomised clinical trial that will aim to investigate the effects of exergames training on postural balance in patients with chronic stroke. METHODS AND ANALYSIS: Forty-two individuals with chronic stroke (>6 months), aged 20-75 years, will be randomised into two groups: the experimental group, which will be subjected to an exergames protocol, and control group, which will undergo a kinesiotherapy protocol. Both protocols are based on postural balance. The intervention will consist of 40-minute sessions two times per week for 10 consecutive weeks. The volunteers will be evaluated before the treatment, at the end of the interventions and 8 weeks thereafter. The primary outcome will be postural balance (Berg Balance Scale, Functional Reach Test, Timed Up and Go test and Centre of Pressure variables) and secondary outcomes will include gait (6 m timed walk and Kinovea Software), cortical activation patterns (electroencephalography Emotiv EPOC), functional independence (Functional Independence Measure), quality of life (Stroke-Specific Quality of Life Scale) and motivation (Intrinsic Motivation Inventory). ETHICS AND DISSEMINATION: This protocol was approved by the Ethics Committee of the Federal University of Rio Grande do Norte (number 3.434.350). The results of the study will be disseminated to participants through social networks and will be submitted to a peer-reviewed journal and scientific meetings. TRIAL REGISTRATION NUMBER: Brazilian Registry of Clinical Trials (RBR-78v9hx).

Reversal of bronchial obstruction with bi-level positive airway pressure and nebulization in patients with acute asthma.

Jet nebulization (JN) and non-invasive mechanical ventilation (NIMV) through bi-level pressure is commonly used in emergency and intensive care of patients experiencing an acute exacerbation of asthma. However, a scientific basis for effect of JN coupled with NIMV is unclear. Objective. To evaluate the effect of jet nebulization administered during spontaneous breathing with that of nebulization with NIV at two levels of inspiratory and expiratory pressures resistance in patients experiencing an acute asthmatic episode. Methods. A prospective, randomized controlled study of 36 patients with severe asthma (forced expiratory volume in 1 second [FEV(1)] less than 60% of predicted) selected with a sample of patients who presented to the emergency department. Subjects were randomized into three groups: control group (nebulization with the use of an unpressured mask), experimental group 1 (nebulization and non-invasive positive pressure with inspiratory positive airway pressure [IPAP] = 15 cm H(2)O, and expiratory positive airway pressure [EPAP] = 5 cm H(2)O), and experimental group 2 (nebulization and non-invasive positive pressure with IPAP = 15 cm H(2)O and EPAP = 10 cm H(2)O). Bronchodilators were administered with JN for all groups. Dependent measures were recorded before and after 30 minutes of each intervention and included respiratory rate (RR), heart rate (HR), oxygen saturation (SpO(2)), peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV(1)), forced vital capacity (FVC), and forced expiratory flow between 25 and 75% (FEF(25-75)). Results. The group E2 showed an increase of the peak expiratory flow (PEF), forced vital capacity (FVC), FEV(1) (p < 0.03) and F(25-75%) (p < 0.000) when compared before and 30 minutes after JN+NIMV. In group E1 the PFE (p < 0.000) reached a significant increase after JN+ NIMV. RR decreased before and after treatment in group E1 only (p = 0.04). Conclusion. Nebulization coupled with NIV in patients with acute asthma has the potential to reduce bronchial obstruction and symptoms secondary to augmented PEF compared with nebulization during spontaneous breathing. In reversing bronchial obstruction, this combination appears to be more efficacious when a low pressure delta is used in combination with a high positive pressure at the end of expiration.