Cognitive Mechanisms of Memory Impairment Following Traumatic Brain Injury

Memory impairment is common following traumatic brain injury (TBI). In recent years, researchers have demonstrated that the processes underlying memory formation (working memory, encoding, consolidation, and retrieval) are interrelated but dissociable events.The following study was designed to determine how these processes contribute to memory impairment following experimental TBI in the rat. Experiment 1 indicated thatTBI induces severe working memory deficits in a delayed non-matching-to-place task.Although all animals displayed intact acquisition, only injured animals displayed poor performance as the delay between the sample and choice phases was increased.Experiment 2 was designed to determine if TBI produces a transient period of posttraumatic amnesia (PTA) following TBI. During the early post-injury period, injured animals displayed intact short-term (3min) object recognition memory but impaired long-term (1 and 24hrs) memory. However, during the chronic post-injury period (days 14-17), no recognition memory deficits were observed in injured animals, indicating thatPTA resolves by 14 days post-injury. Experiment 3 was designed to determine the mechanism of anterograde memory impairment following TBI. Animals were injured and then trained to a pre-determined criterion in a 1 -day water maze procedure.Although injured animals required more trials to reach criterion, the rate of forgetting was identical among sham and injured groups up to 24hrs post-training. This suggests that the amount of information encoded into long-term memory, not more rapid forgetting, is the primary mechanism of anterograde memory impairment following TBI. InExperiment 4, animals were trained in the water maze and then injured 1 (recent memory) or 14 (recent memory) days post-training. Fourteen days post-injury, animals were given a retention probe trial followed by a reminding procedure and a second probe trial. Injured animals in both the recent and remote memory conditions displayed impaired performance on the first probe trial. However, injured animals benefited from the reminding procedure, and animals in the remote memory group were identical to shams during the second probe trial. These results indicate that retrograde memory impairment following TBI is mediated primarily by retrieval deficits at the time of testing, while the quality of the memory trace remains largely intact

Anchored phosphatases modulate glucose homeostasis.

Endocrine release of insulin principally controls glucose homeostasis. Nutrient-induced exocytosis of insulin granules from pancreatic β-cells involves ion channels and mobilization of Ca(2+) and cyclic AMP (cAMP) signalling pathways. Whole-animal physiology, islet studies and live-β-cell imaging approaches reveal that ablation of the kinase/phosphatase anchoring protein AKAP150 impairs insulin secretion in mice. Loss of AKAP150 impacts L-type Ca(2+) currents, and attenuates cytoplasmic accumulation of Ca(2+) and cAMP in β-cells. Yet surprisingly AKAP150 null animals display improved glucose handling and heightened insulin sensitivity in skeletal muscle. More refined analyses of AKAP150 knock-in mice unable to anchor protein kinase A or protein phosphatase 2B uncover an unexpected observation that tethering of phosphatases to a seven-residue sequence of the anchoring protein is the predominant molecular event underlying these metabolic phenotypes. Thus anchored signalling events that facilitate insulin secretion and glucose homeostasis may be set by AKAP150 associated phosphatase activity

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

Abstract Aims/hypothesis Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate’s renal effects in a FIELD washout sub-study. Methods Type 2 diabetic patients (n=9795) aged 50 to 75 years were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin:creatinine ratio) measured at baseline, year 2 and close-out) and estimated GFR, measured 4 to 6 monthly according to the Modification of Diet in Renal Disease study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n=661). Analysis was by intention-to-treat. Results During fenofibrate run-in, plasma creatinine increased by 10.0 µmol/l (p<0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 µmol/l vs 1.89 µmol/l annually, p=0.01), with less estimated GFR loss (1.19 vs 2.03 ml min−1 1.73 m−2 annually, p<0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min−1 1.73 m−2, p=0.065) than on placebo (6.9 ml min−1 1.73 m−2, p<0.001), sparing 5.0 ml min−1 1.73 m−2 (95% CI 2.3-7.7, p<0.001). Greater preservation of estimated GFR with fenofibrate was observed during greater reduction over the active run-in period (pre-randomisation) of triacylglycerol (n=186 vs 170) and baseline hypertriacylglycerolaemia (n=89 vs 80) alone, or combined with low HDL-cholesterol (n=71 vs 60). Fenofibrate reduced urine albumin concentrations and hence albumin:creatinine ratio by 24% vs 12% (p<0.001; mean difference 14% [95% CI 9-18]; p<0.001), with 14% less progression and 18% more albuminuria regression (p<0.001) than in participants on placebo. End-stage renal event frequency was similar (n=21 vs 26, p=0.48). Conclusions/interpretation Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals) and the NHMRC of Australia.Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

Abstract Aims/hypothesis Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate’s renal effects in a FIELD washout sub-study. Methods Type 2 diabetic patients (n=9795) aged 50 to 75 years were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin:creatinine ratio) measured at baseline, year 2 and close-out) and estimated GFR, measured 4 to 6 monthly according to the Modification of Diet in Renal Disease study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n=661). Analysis was by intention-to-treat. Results During fenofibrate run-in, plasma creatinine increased by 10.0 µmol/l (p<0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 µmol/l vs 1.89 µmol/l annually, p=0.01), with less estimated GFR loss (1.19 vs 2.03 ml min−1 1.73 m−2 annually, p<0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min−1 1.73 m−2, p=0.065) than on placebo (6.9 ml min−1 1.73 m−2, p<0.001), sparing 5.0 ml min−1 1.73 m−2 (95% CI 2.3-7.7, p<0.001). Greater preservation of estimated GFR with fenofibrate was observed during greater reduction over the active run-in period (pre-randomisation) of triacylglycerol (n=186 vs 170) and baseline hypertriacylglycerolaemia (n=89 vs 80) alone, or combined with low HDL-cholesterol (n=71 vs 60). Fenofibrate reduced urine albumin concentrations and hence albumin:creatinine ratio by 24% vs 12% (p<0.001; mean difference 14% [95% CI 9-18]; p<0.001), with 14% less progression and 18% more albuminuria regression (p<0.001) than in participants on placebo. End-stage renal event frequency was similar (n=21 vs 26, p=0.48). Conclusions/interpretation Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals) and the NHMRC of Australia.Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals

Targeted Amplicon Sequencing (TAS): A Scalable Next-Gen Approach to Multilocus, Multitaxa Phylogenetics

Next-gen sequencing technologies have revolutionized data collection in genetic studies and advanced genome biology to novel frontiers. However, to date, next-gen technologies have been used principally for whole genome sequencing and transcriptome sequencing. Yet many questions in population genetics and systematics rely on sequencing specific genes of known function or diversity levels. Here, we describe a targeted amplicon sequencing (TAS) approach capitalizing on next-gen capacity to sequence large numbers of targeted gene regions from a large number of samples. Our TAS approach is easily scalable, simple in execution, neither time-nor labor-intensive, relatively inexpensive, and can be applied to a broad diversity of organisms and/or genes. Our TAS approach includes a bioinformatic application, BarcodeCrucher, to take raw next-gen sequence reads and perform quality control checks and convert the data into FASTA format organized by gene and sample, ready for phylogenetic analyses. We demonstrate our approach by sequencing targeted genes of known phylogenetic utility to estimate a phylogeny for the Pancrustacea. We generated data from 44 taxa using 68 different 10-bp multiplexing identifiers. The overall quality of data produced was robust and was informative for phylogeny estimation. The potential for this method to produce copious amounts of data from a single 454 plate (e.g., 325 taxa for 24 loci) significantly reduces sequencing expenses incurred from traditional Sanger sequencing. We further discuss the advantages and disadvantages of this method, while offering suggestions to enhance the approach

Move over Nelly: lessons from 30 years of employment-based initial teacher education in England

Recruiting, preparing and retaining high-quality teachers are recurrent themes of local, national and international education agendas. Traditional university-led forms of teacher education continue to be challenged, and defended, as nations strive to secure a teaching force equipped to achieve high-quality learning outcomes for all students. One commonly adopted policy solution has been the diversification of teacher preparation routes: the alternative certification agenda. In this article, we examine the entire history of one alternative route in place in England from 1997 to 2012, the Graduate Teacher Programme. Using one example of an employment-based programme, we argue that opportunities to engineer innovative and creative spaces in the face of the current teacher preparation reform agenda need to be seized. This case study, which is contextualised in both the international debates about alternative teacher certification routes and the current policy agenda in England, demonstrates the extent to which successive administrations have failed to learn from the lessons of the past in the rush to recycle policies and claim them as their own

Combinations of newly confirmed Glioma-Associated loci link regions on chromosomes 1 and 9 to increased disease risk

<p>Abstract</p> <p>Background</p> <p>Glioblastoma multiforme (GBM) tends to occur between the ages of 45 and 70. This relatively early onset and its poor prognosis make the impact of GBM on public health far greater than would be suggested by its relatively low frequency. Tissue and blood samples have now been collected for a number of populations, and predisposing alleles have been sought by several different genome-wide association (GWA) studies. The Cancer Genome Atlas (TCGA) at NIH has also collected a considerable amount of data. Because of the low concordance between the results obtained using different populations, only 14 predisposing single nucleotide polymorphism (SNP) candidates in five genomic regions have been replicated in two or more studies. The purpose of this paper is to present an improved approach to biomarker identification.</p> <p>Methods</p> <p>Association analysis was performed with control of population stratifications using the EIGENSTRAT package, under the null hypothesis of "no association between GBM and control SNP genotypes," based on an additive inheritance model. Genes that are strongly correlated with identified SNPs were determined by linkage disequilibrium (LD) or expression quantitative trait locus (eQTL) analysis. A new approach that combines meta-analysis and pathway enrichment analysis identified additional genes.</p> <p>Results</p> <p>(i) A meta-analysis of SNP data from TCGA and the Adult Glioma Study identifies 12 predisposing SNP candidates, seven of which are reported for the first time. These SNPs fall in five genomic regions (5p15.33, 9p21.3, 1p21.2, 3q26.2 and 7p15.3), three of which have not been previously reported. (ii) 25 genes are strongly correlated with these 12 SNPs, eight of which are known to be cancer-associated. (iii) The relative risk for GBM is highest for risk allele combinations on chromosomes 1 and 9. (iv) A combined meta-analysis/pathway analysis identified an additional four genes. All of these have been identified as cancer-related, but have not been previously associated with glioma. (v) Some SNPs that do not occur reproducibly across populations are in reproducible (invariant) pathways, suggesting that they affect the same biological process, and that population discordance can be partially resolved by evaluating processes rather than genes.</p> <p>Conclusion</p> <p>We have uncovered 29 glioma-associated gene candidates; 12 of them known to be cancer related (<it>p </it>= 1. 4 × 10^-6), providing additional statistical support for the relevance of the new candidates. This additional information on risk loci is potentially important for identifying Caucasian individuals at risk for glioma, and for assessing relative risk.</p

Tyrannobdella rex N. Gen. N. Sp. and the Evolutionary Origins of Mucosal Leech Infestations

BACKGROUND: Leeches have gained a fearsome reputation by feeding externally on blood, often from human hosts. Orificial hirudiniasis is a condition in which a leech enters a body orifice, most often the nasopharyngeal region, but there are many cases of leeches infesting the eyes, urethra, vagina, or rectum. Several leech species particularly in Africa and Asia are well-known for their propensity to afflict humans. Because there has not previously been any data suggesting a close relationship for such geographically disparate species, this unnerving tendency to be invasive has been regarded only as a loathsome oddity and not a unifying character for a group of related organisms. PRINCIPAL FINDINGS: A new genus and species of leech from Perú was found feeding from the nasopharynx of humans. Unlike any other leech previously described, this new taxon has but a single jaw with very large teeth. Phylogenetic analyses of nuclear and mitochondrial genes using parsimony and Bayesian inference demonstrate that the new species belongs among a larger, global clade of leeches, all of which feed from the mucosal surfaces of mammals. CONCLUSIONS: This new species, found feeding from the upper respiratory tract of humans in Perú, clarifies an expansion of the family Praobdellidae to include the new species Tyrannobdella rex n. gen. n. sp., along with others in the genera Dinobdella, Myxobdella, Praobdella and Pintobdella. Moreover, the results clarify a single evolutionary origin of a group of leeches that specializes on mucous membranes, thus, posing a distinct threat to human health

Diverse University Students Across the United States Reveal Promising Pathways to Hunter Recruitment and Retention

Declining participation in hunting, especially among young adult hunters, affects the ability of state and federal agencies to achieve goals for wildlife management and decreases revenue for conservation. For wildlife agencies hoping to engage diverse audiences in hunter recruitment, retention, and reactivation (R3) efforts, university settings provide unique advantages: they contain millions of young adults who are developmentally primed to explore new activities, and they cultivate a social atmosphere where new identities can flourish. From 2018 to 2020, we surveyed 17,203 undergraduate students at public universities across 22 states in the United States to explore R3 potential on college campuses and assess key demographic, social, and cognitive correlates of past and intended future hunting behavior. After weighting to account for demographic differences between our sample and the larger student population, 29% of students across all states had hunted in the past. Students with previous hunting experience were likely to be white, male, from rural areas or hunting families, and pursuing degrees related to natural resources. When we grouped students into 1 of 4 categories with respect to hunting (i.e., non-hunters [50%], potential hunters [22%], active hunters [26%], and lapsed hunters [3%]), comparisons revealed differences based on demographic attributes, beliefs, attitudes, and behaviors. Compared to active hunters, potential hunters were more likely to be females or racial and ethnic minorities, and less likely to experience social support for hunting. Potential hunters valued game meat and altruistic reasons for hunting, but they faced unique constraints due to lack of hunting knowledge and skills. Findings provide insights for marketing and programming designed to achieve R3 objectives with a focus on university students. © 2021 The Wildlife Society

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy