14,179 research outputs found
Administration of Tramadol or Buprenorphine via the drinking water for post-operative analgesia in a mouse-osteotomy model
Adequate analgesia is essential whenever pain might occur in animal experiments. Unfortunately, the selection of suitable analgesics for mice in bone-linked models is limited. Here, we evaluated two analgesics - Tramadol [0.1âmg/ml (Tlow) vs. 1âmg/ml (Thigh)] and Buprenorphine (Bup; 0.009âmg/ml) - after a pre-surgical injection of Buprenorphine, in a mouse-osteotomy model. The aim of this study was to verify the efficacy of these opioids in alleviating pain-related behaviors, to provide evidence for adequate dosages and to examine potential side effects. High concentrations of Tramadol affected water intake, drinking frequency, food intake and body weight negatively in the first 2-3 days post-osteotomy, while home cage activity was comparable between all groups. General wellbeing parameters were strongly influenced by anesthesia and analgesics. Model-specific pain parameters did not indicate more effective pain relief at high concentrations of Tramadol. In addition, ex vivo high-resolution micro computed tomography (”CT) analysis and histology analyzing bone healing outcomes showed no differences between analgesic groups with respect to newly formed mineralized bone, cartilage and vessels. Our results show that high concentrations of Tramadol do not improve pain relief compared to low dosage Tramadol and Buprenorphine, but rather negatively affect animal wellbeing
Ingested insecticide to control Aedes aegypti: developing a novel dried attractive toxic sugar bait device for intra-domiciliary control
© 2020 The Author(s). Background: Illnesses transmitted by Aedes aegypti (Linnaeus, 1762) such as dengue, chikungunya and Zika comprise a considerable global burden; mosquito control is the primary public health tool to reduce disease transmission. Current interventions are inadequate and insecticide resistance threatens the effectiveness of these options. Dried attractive bait stations (DABS) are a novel mechanism to deliver insecticide to Ae. aegypti. The DABS are a high-contrast 28 inch2 surface coated with dried sugar-boric acid solution. Aedes aegypti are attracted to DABS by visual cues only, and the dried sugar solution elicits an ingestion response from Ae. aegypti landing on the surface. The study presents the development of the DABS and tests of their impact on Ae. aegypti mortality in the laboratory and a series of semi-field trials. Methods: We conducted multiple series of laboratory and semi-field trials to assess the survivability of Ae. aegypti mosquitoes exposed to the DABS. In the laboratory experiments, we assessed the lethality, the killing mechanism, and the shelf life of the device through controlled experiments. In the semi-field trials, we released laboratory-reared female Ae. aegypti into experimental houses typical of peri-urban tropical communities in South America in three trial series with six replicates each. Laboratory experiments were conducted in Quito, Ecuador, and semi-field experiments were conducted in Machala, Ecuador, an area with abundant wild populations of Ae. aegypti and endemic arboviral transmission. Results: In the laboratory, complete lethality was observed after 48 hours regardless of physiological status of the mosquito. The killing mechanism was determined to be through ingestion, as the boric acid disrupted the gut of the mosquito. In experimental houses, total mosquito mortality was greater in the treatment house for all series of experiments (P \u3c 0.0001). Conclusions: The DABS devices were effective at killing female Ae. aegypti under a variety of laboratory and semi-field conditions. DABS are a promising intervention for interdomiciliary control of Ae. aegypti and arboviral disease prevention.[Figure not available: see fulltext.
Targeting Intracellular Calcium Stores Alleviates Neurological Morbidities in a DFP-Based Rat Model of Gulf War Illness
Gulf War Illness (GWI) is a chronic multi-symptom disorder afflicting the veterans of the First Gulf War, and includes neurological symptoms characterized by depression and memory deficits. Chronic exposure to organophosphates (OP) is considered a leading cause for GWI, yet its pathobiology is not fully understood. We recently observed chronic elevations in neuronal Ca2+ levels ([Ca2+]i) in an OP- diisopropyl fluorophosphate (DFP) based rat model for GWI. This study was aimed at identifying mechanisms underlying elevated [Ca2+]i in this DFP model and investigating whether their therapeutic targeting could improve GWI-like neurological morbidities. Male Sprague-Dawley rats (9-wks) were exposed to DFP (0.5âmg/kg, s.c, 1x-daily for 5-d) and at 3-mos post DFP exposure, behavior was assessed and rats were euthanized for protein estimations and ratiometric Fura-2 [Ca2+]i estimations in acutely dissociated hippocampal neurons. In DFP rats, a sustained elevation in intracellular Ca2+ levels occurred, and pharmacological blockade of Ca2+-induced Ca2+-release mechanisms significantly lowered elevated [Ca2+]i in DFP neurons. Significant reductions in the protein levels of the ryanodine receptor (RyR) stabilizing protein Calstabin2 were also noted. Such a post-translational modification would render RyR leaky resulting in sustained DFP [Ca2+]i elevations. Antagonism of RyR with levetiracetam significantly lower elevated [Ca2+]i in DFP neurons and improved GWI-like behavioral symptoms. Since Ca2+ is a major second messenger molecule, such chronic increases in its levels could underlie pathological synaptic plasticity that expresses itself as GWI morbidities. Our studies show that treatment with drugs targeted at blocking intracellular Ca2+ release could be effective therapies for GWI neurological morbidities
Gastroprotective effects of oral nucleotide administration
BACKGROUND AND AIMS: Nucleotides form the building blocks of DNA and are marketed as dietary supplements, alone or in combination with other ingredients, to promote general health. However, there has been only limited scientific study regarding the true biological activity of orally administered nucleotides. We therefore tested their efficacy in a variety of models of epithelial injury and repair. METHODS: Effects on proliferation ([(3)H] thymidine incorporation) and restitution (cell migration of wounded monolayers) were analysed using HT29 and IEC6 cells. The ability of a nucleotide mixture to influence gastric injury when administered orally and subcutaneously was analysed using a rat indomethacin (20â
mg/kg) restraint model. RESULTS: In both cell lines, cell migration was increased by approximately twofold when added at 1â
mg/ml (p<0.01); synergistic responses were seen when a mixture of nucleotides was used. Cell proliferation was stimulated by adenosine monophosphate (AMP) in HT29, but not in IEC6, cells. Gastric injury was reduced by approximately 60% when gavaged at 4â16â
mg/ml (p<0.05), concentrations similar to those likely to be found in consumers taking nucleotide supplements. Systemic administration of nucleotides was unhelpful. CONCLUSIONS: Nucleotides possess biological activity when analysed in a variety of models of injury and repair and could provide a novel inexpensive approach for the prevention and treatment of the injurious effects of non steroidal antiâinflammatory drugs and other ulcerative conditions of the bowel. Further studies on their potential benefits (and risks) appear justified
Improving transparency and scientific rigor in academic publishing.
Progress in basic and clinical research is slowed when researchers fail to provide a complete and accurate report of how a study was designed, executed, and the results analyzed. Publishing rigorous scientific research involves a full description of the methods, materials, procedures, and outcomes. Investigators may fail to provide a complete description of how their study was designed and executed because they may not know how to accurately report the information or the mechanisms are not in place to facilitate transparent reporting. Here, we provide an overview of how authors can write manuscripts in a transparent and thorough manner. We introduce a set of reporting criteria that can be used for publishing, including recommendations on reporting the experimental design and statistical approaches. We also discuss how to accurately visualize the results and provide recommendations for peer reviewers to enhance rigor and transparency. Incorporating transparency practices into research manuscripts will significantly improve the reproducibility of the results by independent laboratories
Maternal Immune Activation Causes Behavioral Impairments and Altered Cerebellar Cytokine and Synaptic Protein Expression
Emerging epidemiology studies indicate that maternal immune activation (MIA) resulting from inflammatory stimuli such as viral or bacterial infections during pregnancy serves as a risk factor for multiple neurodevelopmental disorders including autism spectrum disorders and schizophrenia. Although alterations in the cortex and hippocampus of MIA offspring have been described, less evidence exists on the impact on the cerebellum. Here, we report altered expression of cytokines and chemokines in the cerebellum of MIA offspring, including increase in the neuroinflammatory cytokine TNFα and its receptor TNFR1. We also report reduced expression of the synaptic organizing proteins cerebellin-1 and GluRΎ2. These synaptic protein alterations are associated with a deficit in the ability of cerebellar neurons to form synapses and an increased number of dendritic spines that are not in contact with a presynaptic terminal. These impairments are likely contributing to the behavioral deficits in the MIA exposed offspring
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Early neuronal accumulation of DNA double strand breaks in Alzheimer's disease.
The maintenance of genomic integrity is essential for normal cellular functions. However, it is difficult to maintain over a lifetime in postmitotic cells such as neurons, in which DNA damage increases with age and is exacerbated by multiple neurological disorders, including Alzheimer's disease (AD). Here we used immunohistochemical staining to detect DNA double strand breaks (DSBs), the most severe form of DNA damage, in postmortem brain tissues from patients with mild cognitive impairment (MCI) or AD and from cognitively unimpaired controls. Immunostaining for ÎłH2AX-a post-translational histone modification that is widely used as a marker of DSBs-revealed increased proportions of ÎłH2AX-labeled neurons and astrocytes in the hippocampus and frontal cortex of MCI and AD patients, as compared to age-matched controls. In contrast to the focal pattern associated with DSBs, some neurons and glia in humans and mice showed diffuse pan-nuclear patterns of ÎłH2AX immunoreactivity. In mouse brains and primary neuronal cultures, such pan-nuclear ÎłH2AX labeling could be elicited by increasing neuronal activity. To assess whether pan-nuclear ÎłH2AX represents DSBs, we used a recently developed technology, DNA damage in situ ligation followed by proximity ligation assay, to detect close associations between ÎłH2AX sites and free DSB ends. This assay revealed no evidence of DSBs in neurons or astrocytes with prominent pan-nuclear ÎłH2AX labeling. These findings suggest that focal, but not pan-nuclear, increases in ÎłH2AX immunoreactivity are associated with DSBs in brain tissue and that these distinct patterns of ÎłH2AX formation may have different causes and consequences. We conclude that AD is associated with an accumulation of DSBs in vulnerable neuronal and glial cell populations from early stages onward. Because of the severe adverse effects this type of DNA damage can have on gene expression, chromatin stability and cellular functions, DSBs could be an important causal driver of neurodegeneration and cognitive decline in this disease
Dietary Prebiotics and Bioactive Milk Fractions Improve NREM Sleep, Enhance REM Sleep Rebound and Attenuate the Stress-Induced Decrease in Diurnal Temperature and Gut Microbial Alpha Diversity.
Severe, repeated or chronic stress produces negative health outcomes including disruptions of the sleep/wake cycle and gut microbial dysbiosis. Diets rich in prebiotics and glycoproteins impact the gut microbiota and may increase gut microbial species that reduce the impact of stress. This experiment tested the hypothesis that consumption of dietary prebiotics, lactoferrin (Lf) and milk fat globule membrane (MFGM) will reduce the negative physiological impacts of stress. Male F344 rats, postnatal day (PND) 24, received a diet with prebiotics, Lf and MFGM (test) or a calorically matched control diet. Fecal samples were collected on PND 35/70/91 for 16S rRNA sequencing to examine microbial composition and, in a subset of rats; Lactobacillus rhamnosus was measured using selective culture. On PND 59, biotelemetry devices were implanted to record sleep/wake electroencephalographic (EEG). Rats were exposed to an acute stressor (100, 1.5 mA, tail shocks) on PND 87 and recordings continued until PND 94. Test diet, compared to control diet, increased fecal Lactobacillus rhamnosus colony forming units (CFU), facilitated non-rapid eye movement (NREM) sleep consolidation (PND 71/72) and enhanced rapid eye movement (REM) sleep rebound after stressor exposure (PND 87). Rats fed control diet had stress-induced reductions in alpha diversity and diurnal amplitude of temperature, which were attenuated by the test diet (PND 91). Stepwise multiple regression analysis revealed a significant linear relationship between early-life Deferribacteres (PND 35) and longer NREM sleep episodes (PND 71/72). A diet containing prebiotics, Lf and MFGM enhanced sleep quality, which was related to changes in gut bacteria and modulated the impact of stress on sleep, diurnal rhythms and the gut microbiota
Biochemical Effects of Exercise on a Fasciocutaneous Flap in a Rat Model.
Importance: An overwhelming amount of data suggest that cardiovascular exercise has a positive effect on the mind and body, although the precise mechanism is not always clear.
Objective: To assess the clinical and biochemical effects of voluntary cardiovascular exercise on pedicled flaps in a rodent model.
Design, Setting, and Participants: Eighteen adult Sprague-Dawley male rats were randomized into a resting animal group (RAG) (n=9) and an exercise animal group (EAG) (n=9) for 14 days (July 23, 2013, through July 30, 2013). A pedicled transposition flap was performed on the ventral surface of the rat, and biopsy specimens were taken from the proximal, middle, and distal portions on postoperative days 0, 2, 5, and 9. Flap survival was analyzed planimetrically, and biopsy specimens were analyzed by hematoxylin-eosin-stained microscopy and immunoblotting. The housing, exercise, surgery, and analysis of the rats were conducted at a single basic science research laboratory at the tertiary care center campus of Thomas Jefferson University in Philadelphia, Pennsylvania.
Exposures: The rats were caged for 14 days or housed in a cage connected to an exercise wheel and pedometer.
Main Outcomes and Measures: Study measures were gross and micrographic necrosis and expression of proteins within cell survival and apoptosis pathways.
Results: A total of 18 rats were studied, 9 in the RAG and 9 in the EAG. the mean (SEM) amount of necrosis in flaps was 41.3% (3%) in the RAG rats and 10.5% (3.5%) in the EAG rats (Pâ\u3câ.001). Immunoblotting revealed increased Caspase-9 activity resulting in poly-(adenosine diphosphate-ribose) polymerase 1 cleavage in the RAG vs the EAG, as well as lower phosphorylated protein kinase B (also known as Akt), signal transducer and activator of transcription 3, and total B-cell leukemia/lymphoma 2 protein levels. Throughout the postoperative period, the cumulative vascular endothelial growth factor A levels of the EAG flaps were significantly higher than those of the RAG flaps (2.30 vs 1.25 fold induction [FI], Pâ=â.002), with differences of 2.76 vs 1.54 FI in the proximal segment, 2.40 vs 1.20 FI in the middle segment, and 1.90 vs 0.79 FI in the distal segment. A similar response was noted when comparing phosphorylated Akt, with cumulative mean (SEM) p-Akt expression levels of 0.62 (0.04) for RAG and 1.98 (0.09) for EAG (Pâ=â.002 between the 2 groups).
Conclusions and Relevance: Voluntary preoperative exercise improves survival in pedicled fasciocutaneous flaps; the EAG rats had less necrosis, decreased apoptotic markers, and increased amounts of vascular endothelial growth factor A and prosurvival proteins. These results have implications to increase flap survival in other mammal populations, such as humans.
Level of Evidence: 3
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