Tachyphylaxis in 12-0-Tetradecanoylphorbol Acetate- and Arachidonic Acid-Induced Ear Edema

12-0-Tetradecanoylphorbol acetate (TPA) applied to mouse ears rapidly induces an edema which is maximal by 6 hr but has substantially waned by 24 hr. (This is in contrast to many inflammatory agents that cause a prolonged edema lasting many days.) Reapplication of TPA at 16-24 hr will not provoke a second edematous response although increased erythema is evident. Arachidonic acid (AA) applied to mouse ears (4 mg) provokes an even more rapid edema which is maximal at 1 hr and has substantially waned by 6 hr. Reapplication of AA at 3-24 hr also will not provoke a second edematous response although, again, increased erythema does result. Pretreatment of ears with AA results in inhibition of the edema response to subsequent application of TPA, and TPA pretreatment moderately inhibits a subsequent response to AA. TPA-induced edema can be delayed by agents such as naproxen, an inhibitor of AA cyclooxygenase. In contrast, AA-induced edema is inhibited only by agents, such as phenidone, that inhibit both cyclooxygenase and lipoxygenase. The data suggest that the edemas result from interaction of the products of the cyclooxygenase and lipoxygenase pathways of AA metabolism. The lack of secondary edema response appears to be related to the inability of TPA or AA to reinduce vascular permeability. The effect is specific to AA and TPA; responses to xylene or anthralin are unaffected by TPA or AA pretreatment. It is postulated that the tachyphylactic effects observed involve lipoxygenase metabolites of AA

Soluble tau species, not neurofibrillary aggregates, disrupt neural system integration in a tau transgenic model

Neurofibrillary tangles are a feature of Alzheimer disease and other tauopathies, and while they are generally believed to be markers of neuronal pathology, there is little evidence evaluating whether tangles directly impact neuronal function. To investigate the response of cells in hippocampal circuits to complex behavioral stimuli, we used an environmental enrichment paradigm to induce expression of an immediate-early gene, Arc, in the rTg4510 mouse model of tauopathy. These mice reversibly overexpress P301L tau and exhibit substantial neurofibrillary tangle deposition, neuronal loss, and memory deficits. Employing fluorescent in situ hybridization to detect Arc mRNA, we found that rTg4510 mice have impaired hippocampal Arc expression both without stimulation and in response to environmental enrichment; this likely reflects the combination of functional impairments of existing neurons and loss of neurons. However, tangle-bearing cells were at least as likely as non-tangle-bearing neurons to exhibit Arc expression in response to enrichment. Transgene suppression with doxycycline for 6 weeks resulted in increased percentages of Arc-positive cells in rTg4510 brains compared to untreated transgenics, restoring enrichment-induced Arc mRNA levels to that of wild-type controls despite the continued presence of neurofibrillary pathology. We interpret these data to indicate that soluble tau contributes to impairment of hippocampal function, while tangles do not preclude neurons from responding in a functional circuit

The motivation of the successful African-American adolescent male

This review of the literature looks at the motivating factors for the academic success and failure for the African American adolescent male. The questions which are addressed in this review are: 1. Are there multiple levels of self-esteem? 2. Is there a correlation between ·self-esteem and motivation for academic achievement? 3. What effect does the school and its environment have on academic success? 4. What impact does the African American family have on the success of young adolescent males? Suggestions based on the findings are that as middle schools restructure they will need to focus on the academic and social needs of the African American adolescent male and all children of color. New strategies must be developed to raise academic self-esteem, cultural pride, and to provide a greater sense of school membership through parent/community involvement. When looking at the needs of the African American adolescent male or any student at risk, the restructured middle school must focus on the development and implementation of the following programs: African American male mentoring; the recruitment of look like me educators; celebration of diversity in the classroom; relevant curriculum with alternative assessment; staff development; parent/teacher communication network; and the community as a partner in education

Alzheimer's disease: synapses gone cold

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by insidious cognitive decline and memory dysfunction. Synapse loss is the best pathological correlate of cognitive decline in AD and mounting evidence suggests that AD is primarily a disease of synaptic dysfunction. Soluble oligomeric forms of amyloid beta (Aβ), the peptide that aggregates to form senile plaques in the brain of AD patients, have been shown to be toxic to neuronal synapses both in vitro and in vivo. Aβ oligomers inhibit long-term potentiation (LTP) and facilitate long-term depression (LTD), electrophysiological correlates of memory formation. Furthermore, oligomeric Aβ has also been shown to induce synapse loss and cognitive impairment in animals. The molecular underpinnings of these observations are now being elucidated, and may provide clear therapeutic targets for effectively treating the disease. Here, we review recent findings concerning AD pathogenesis with a particular focus on how Aβ impacts synapses

Floppy aortic graft reconstruction for germ cell tumor invasion of the infrarenal aorta

AbstractSignificant aortic invasion by metastatic nonseminomatous germ cell tumors can present difficult problems intraoperatively in attempted curative retroperitoneal lymph node dissection. Aortic replacement with Dacron graft has been a successful method of dealing with this predicament. We describe a new approach of intraoperative floppy aortic graft reconstruction in a young patient with testicular germ cell cancer in whom a 14 cm pseudoaneurysm involving the infrarenal aorta developed after four courses of preoperative chemotherapy. This technique prevents significant lower extremity and pelvic ischemia during resection of the aorta and retroperitoneal tumor while providing the urologic surgeon with excellent exposure and minimal interference from the aortic graft. (J Vasc Surg 2003;37:889-91.

The Healthy Start scheme in England “is a lifeline for families but many are missing out”: a rapid qualitative analysis

Background Healthy Start (HS) is a government scheme in England, Wales and Northern Ireland that offers a financial payment card and free vitamins to families experiencing low income. Pregnant women and families with children < 4 years can use the HS card to buy fruit, vegetables, cow’s milk, infant formula and pulses. HS was fully digitalised in March 2022. While digitalisation has improved the user experience for many families, in the context of the cost-of-living crisis and increasing dietary inequalities, it is important to understand why HS is not reaching more families. This study aimed to (i) assess the perceptions and experiences of HS from stakeholders across the system including those who promote, implement and are eligible for HS, and (ii) identify recommendations to improve the scheme’s effectiveness and uptake. Methods The study design was a post-implementation rapid qualitative evaluation using stakeholder interviews. Data were collected between January and June 2023 via semi‐structured interviews (50% online; 50% in person) with 112 stakeholders, including parents (n = 59), non‐government organisations (n = 13), retailers (n = 11) and health and community professionals (n = 29) at national and local levels. Findings were confirmed by a sub-sample of participants. Results Six core themes cut across stakeholders’ perceptions and experiences, and stakeholders collectively outlined seven recommendations they felt could be acted upon to maximise uptake and efficiency of HS, with actions at both national and local levels. A novel finding from this study is that raising awareness about HS alone is unlikely to result automatically or universally in higher uptake rate. Recommendations include: continuing to provide this scheme that is universally valued; the need for many families to be provided with a helping hand to successfully complete the application; reframing of the scheme as a child’s right to food and development to ensure inclusivity; improved leadership, coordination and accountability at both national and local levels. Conclusions HS provides benefits for child development and family wellbeing. The study’s recommendations should be actioned by national and local governments to enable all families eligible for the scheme to benefit from this nutritional safety net

Wheel running from a juvenile age delays onset of specific motor deficits but does not alter protein aggregate density in a mouse model of Huntington's disease

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background Huntington's disease (HD) is a neurodegenerative disorder predominantly affecting the cerebral cortex and striatum. Transgenic mice (R6/1 line), expressing a CAG repeat encoding an expanded polyglutamine tract in the N-terminus of the huntingtin protein, closely model HD. We have previously shown that environmental enrichment of these HD mice delays the onset of motor deficits. Furthermore, wheel running initiated in adulthood ameliorates the rear-paw clasping motor sign, but not an accelerating rotarod deficit. Results We have now examined the effects of enhanced physical activity via wheel running, commenced at a juvenile age (4 weeks), with respect to the onset of various behavioral deficits and their neuropathological correlates in R6/1 HD mice. HD mice housed post-weaning with running wheels only, to enhance voluntary physical exercise, have delayed onset of a motor co-ordination deficit on the static horizontal rod, as well as rear-paw clasping, although the accelerating rotarod deficit remains unaffected. Both wheel running and environmental enrichment rescued HD-induced abnormal habituation of locomotor activity and exploratory behavior in the open field. We have found that neither environment enrichment nor wheel running ameliorates the shrinkage of the striatum and anterior cingulate cortex (ACC) in HD mice, nor the overall decrease in brain weight, measured at 9 months of age. At this age, the density of ubiquitinated protein aggregates in the striatum and ACC is also not significantly ameliorated by environmental enrichment or wheel running. Conclusion These results indicate that enhanced voluntary physical activity, commenced at an early presymptomatic stage, contributes to the positive effects of environmental enrichment. However, sensory and cognitive stimulation, as well as motor stimulation not associated with running, may constitute major components of the therapeutic benefits associated with enrichment. Comparison of different environmental manipulations, performed in specific time windows, can identify critical periods for the induction of neuroprotective 'brain reserve' in animal models of HD and related neurodegenerative diseases.Published versio