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Adapting the classic line from the 1967 film Cool Hand Luke, the title is meant to convey that implementation science (IS), like other fields, has not been embracing replication studies, which is a key component to the open science movement. The purpose of this article is to review what is known about replication of implementation trials and identify the gaps and next steps to continue increasing the transparency, openness, and replicability of implementation research. After presenting an overview of study replication and how it is a key component of open science, the article will examine how replication of implementation studies has (or more accurately has not) been approached in IS. As will be discussed, replication in IS shares some challenges with studies that attempt to replicate interventions, but also presents unique challenges. This article discusses different types of replications (e.g., direct vs. conceptual) and how they can benefit the field of IS. The article then presents a specific example of an implementation strategy called Getting To Outcomes© to describe how to design a replication study and interpret the results. The article ends with multiple options implementation scientists could consider to improve the likelihood and quality of replication studies. The discussion also envisions how implementation science can enable researchers and practitioners to work together in real-world contexts to encourage wide replication of implementation studies and advance the goal of improving public health.Polycystic ovary syndrome (PCOS) is a common disorder affecting childbearing-age women, and is associated with reproductive and metabolic disturbances. The present study aimed to systematically review current animal studies and randomized placebo-controlled clinical trials (RCT) regarding the effects of resveratrol, a natural polyphenolic compound, on PCOS features. Tanespimycin concentration PubMed, Scopus, Web of Knowledge, and Google Scholar were comprehensively searched until December 2020. All original animal articles and RCTs evaluating the effects of resveratrol on PCOS were eligible for the review. Out of 289 initial records, eight animal studies and three RCTs met our inclusion criteria. Most of the included animal studies reported beneficial effects of resveratrol on the histomorphological features, sex hormones and gonadotropins, glycemic control, inflammation, and oxidative stress. Resveratrol also ameliorated ovarian volume, high-quality oocyte rate, high-quality embryo rate, androgens and gonadotropins concentrations, angiogenic factors levels, and endoplasmic reticulum stress in PCOS patients. Upregulation of sirtuin-1 was an examined mechanism proposed for some observed effects of resveratrol. The current literature is limited to conclude the beneficial effects of resveratrol on the management of PCOS. Although, according to the promising results of the animal studies and limited RCTs, resveratrol might be an effective phytochemical in PCOS control, especially regarding hormonal and reproductive abnormalities. More mechanistic studies and RCTs are warranted to obvious whether resveratrol can be prescribed in the clinical situation.Rapid eye movement (REM) sleep is implicated learning and memory (L/M) functions and hippocampal long-term potentiation (LTP). Here, we demonstrate that REM sleep deprivation (REMSD)-induced impairment of contextual fear memory in mouse is linked to a reduction in hexosamine biosynthetic pathway (HBP)/O-GlcNAc flux in mouse brain. In mice exposed to REMSD, O-GlcNAcylation, and O-GlcNAc transferase (OGT) were downregulated while O-GlcNAcase was upregulated compared to control mouse brain. Foot shock fear conditioning (FC) induced activation of protein kinase A (PKA) and cAMP response element binding protein (CREB), which were significantly inhibited in brains of the REMSD group. Intriguingly, REMSD-induced defects in L/M functions and FC-induced PKA/CREB activation were restored upon increasing O-GlcNAc cycling with glucosamine (GlcN) or Thiamet G. Furthermore, Thiamet G restored the REMSD-induced decrease in dendritic spine density. Suppression of O-GlcNAcylation by the glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitor, 6-diazo-5-oxo-L-norleucine (DON), or OGT inhibitor, OSMI-1, impaired memory function, and inhibited FC-induced PKA/CREB activation. DON additionally reduced the amplitude of baseline field excitatory postsynaptic potential (fEPSP) and magnitude of long-term potentiation (LTP) in normal mouse hippocampal slices. To our knowledge, this is the first study to provide comprehensive evidence of dynamic O-GlcNAcylation changes during the L/M process in mice and defects in this pathway in the brain of REM sleep-deprived mice. Our collective results highlight HBP/O-GlcNAc cycling as a novel molecular link between sleep and cognitive function.Chemotherapy-induced neuropathy (CIN) is a major dose-limiting side effect of anticancer therapy that can compel therapy discontinuation. Inadequate analgesic efficacy of current pharmacological approaches requires the identification of innovative therapeutics and, hence, the purpose of this study is to conduct a preclinical evaluation of the efficacy of DDD-028, a versatile pentacyclic pyridoindole derivative, against paclitaxel-induced neuropathic pain. In two separate experiments, DDD-028 was administered per os acutely (1-25 mg kg-1) or repeatedly (10 mg kg-1) in paclitaxel-treated rats. The response to mechanical noxious stimulus (paw pressure) as well as to non-noxious mechanical (von Frey) and thermal (cold plate) stimuli was investigated. Acute administration of DDD-028 induced a dose-dependent anti-neuropathic pain effect in all tests performed. Further, repeated daily treatment for 18 consecutive days (starting the first day of paclitaxel administration) significantly reduced the development of pain over time without the development of tolerance to the anti-hyperalgesic effect. Ex vivo analysis showed that DDD-028 was able to reduce oxidative damage of dorsal root ganglia as evidenced by the increase in the level of carbonylated proteins and the decrease in catalase activity. In the lumbar spinal cord, periaqueductal gray matter, thalamus, and somatosensory cortex 1, DDD-28 significantly prevented the activation of microglia and astrocytes. The pharmacodynamic study revealed that the pain-relieving effects of DDD-028 were fully blocked by both the non-selective nicotinic receptor (nAChR) antagonist mecamylamine and by the selective α7 nAChR antagonist methyllycaconitine. In conclusion, DDD-028 was active in reducing paclitaxel-induced neuropathic pain after single or repeated administrations without tolerance development and displaying a double symptomatic and neuroprotective profile. DDD-028 could represent a valuable candidate for the treatment of CIN.Although doxorubicin (Dox) is an effective chemotherapy medication used extensively in the treatment of breast cancer, it frequently causes debilitating neurological deficits known as chemobrain. Donepezil (DPZ), an acetylcholinesterase inhibitor, provides therapeutic benefits in various neuropathological conditions. However, comprehensive mechanistic insights regarding the neuroprotection of DPZ on cognition and brain pathologies in a Dox-induced chemobrain model remain obscure. Here, we demonstrated that Dox-treated rats manifested conspicuous cognitive deficits and developed chemobrain pathologies as indicated by brain inflammatory and oxidative insults, glial activation, defective mitochondrial homeostasis, increased potential lesions associated with Alzheimer's disease, disrupted neurogenesis, loss of dendritic spines, and ultimately neuronal death through both apoptosis and necroptosis. Intervention with DPZ co-treatment completely restored cognitive function by attenuating these pathological conditions induced by DOX. We also confirmed that DPZ treatment does not affect the anti-cancer efficacy of Dox in breast cancer cells. Together, our findings suggest that DPZ treatment confers potential neuroprotection against Dox-induced chemobrain.
Microvascular dysfunction is the key element in the pathogenesis of systemic sclerosis (SSc), whereas the contribution of large and medium size vessel abnormalities is yet to be established. The aim of the present study is to assess the association between micro- and macrovascular function by utilizing a broad spectrum of assessments of vascular performance.
We included consecutive, consenting SSc patients who underwent nailfold video capillaroscopy (NVC) for microcirculation evaluation. Peripheral and central systolic and diastolic blood pressure, carotid intima-media thickness (cIMT), aortic augmentation index (AIx) corrected for a heart rate of 75 beats per minute (AIx-75), and carotid-femoral pulse wave velocity (PWV) were also performed to assess macrovascular function. Cardiovascular risk disease (CVD) algorithms were also calculated and included in the analysis.
A total of 81 patients (6 males) were studied with mean age 55.44 ± 13.40years. Reduced capillary density was inversely correlated with igher CVD risk in SSc patients.The aim of present research aims to fabricate a system of enteric coating of hydrogel beads with pH-sensitive polymer, which shows solubility at pH > 7, and explore their potential to target the colon for drug delivery. Hydrogel beads were fabricated through the extrusion-dripping technique followed by ion gelation crosslinking. Moreover, freeze-thaw cycle was implemented for crosslinking of polyvinyl alcohol (PVA)/Ca-alginate blend beads. The oil-in-oil solvent evaporation method was adopted for the Eudragit coating of hydrogel beads using different coat core ratios (41 or 81). Coated and uncoated hydrogel beads were evaluated by in vitro physicochemical properties, swelling and drug release behaviours, and in vivo pharmacokinetics, swelling, and toxicity evaluation. Diclofenac sodium was loaded as an experimental drug. Drug entrapment efficiency for the PVA/Ca-alginate beads was calculated as 98%, and for Ca-alginate beads, it came out to a maximum of 74%. Drug release study at various pH suggested that, unlike uncoated hydrogel beads, the coated beads delay the release of diclofenac sodium in low pH of the gastric and intestinal environment, thus targeting the colon for the drug release. It was concluded that Eudragit S-100-coated hydrogel beads could serve as a more promising and reliable way to target the colon for drug delivery.Graphical abstract.In the past, ecological research mainly omitted the sexual and developmental variability of mite communities, and therefore could not fully reflect the actual state and function of mite communities in the ecosystems studied. The aim here was to analyze how habitat conditions (mixed vs. monoculture stands) and single-species litter of 14 tree species (in mixed stands) affect the sex and developmental stages of Mesostigmata mites living on the decomposing litter. The research was conducted in 2011-2016, at the Bełchatów Lignite Mine external spoil heap (Central Poland) in mixed stands growing on the spoil heap, as well as in pine and birch monoculture stands growing on the spoil heap and an adjacent forest area. We found significant influences of habitat on females, males and juveniles. Additionally, we found that soil mean temperature had a significant effect on males and juveniles, but not on females. Moreover, despite the insignificant influence of litter species on mite communities, we found that percentage litter mass loss significantly affected female and juvenile mites.
Homepage: https://www.selleckchem.com/products/17-AAG(Geldanamycin).html
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