EVOLUTION: Of Mice . . .

Stroke, the third leading cause of death and disability worldwide, is undergoing a change in perspective with the emergence of new ideas on neurodegeneration The concept that stroke is a disorder solely of blood vessels has been expanded to include the effects of a detrimental interaction between glia, neurons, vascular cells, and matrix components, which is collectively referred to as the neurovascular unit Following the acute stroke, the majority of which are ischemic, there is secondary neuroinflammation that both promotes further injury, resulting in cell death, but conversely plays a beneficial role, by promoting recovery The proinflammatory signals from immune mediators rapidly activate resident cells and influence infiltration of a wide range of inflammatory cells (neutrophils, monocytes/macrophages, different subtypes of T cells, and other inflammatory cells) into the ischemic region exacerbating brain damage In this review, we discuss how neuroinflammation has both beneficial as well as detrimental roles and recent therapeutic strategies to combat pathological responses Here, we also focus on time-dependent entry of immune cells to the ischemic area and the impact of other pathological mediators, including oxidative stress, excitotoxicity, matrix metalloproteinases (MMPs), high-mobility group box 1 (HMGB1), arachidonic acid metabolites, mitogen-activated protein kinase (MAPK), and post-translational modifications that could potentially perpetuate ischemic brain damage after the acute injury Understanding the time-dependent role of inflammatory factors could help in developing new diagnostic, prognostic, and therapeutic neuroprotective strategies for post-stroke inflammation

/pdf/neuroinflammation-friend-and-foe-for-ischemic-stroke-3ivhensbsu.pdf

Neuroinflammation: friend and foe for ischemic stroke

結腸癌術後の早期離床・早期経口摂取に関するProspective Randomized Trial

Highly impacting oral and poster presentations wherein new treatment modalities for coronary artery disease, heart failure and other common cardiovascular diseases were presented throughout the AHA Scientific Sessions 2012, including new developments in the area of lipid-modifying therapies that starred one of the high-impact late-breaking clinical trial sessions during the conference. A summary of the most relevant findings among the over 4,000 abstracts presented during the meeting are reported in the following report.

A report from the American Heart Association Scientific Sessions 2012 (November 3-7 - Los Angeles, California, USA).

The cerebral ischemia injury can result in neuronal death and/or functional impairment, which leads to further damage and dysfunction after recovery of blood supply. Cerebral ischemia/reperfusion injury (CIRI) often causes irreversible brain damage and neuronal injury and death, which involves many complex pathological processes including oxidative stress, amino acid toxicity, the release of endogenous substances, inflammation and apoptosis. Oxidative stress and inflammation are interactive and play critical roles in ischemia/reperfusion injury in the brain. Oxidative stress is important in the pathological process of ischemic stroke and is critical for the cascade development of ischemic injury. Oxidative stress is caused by reactive oxygen species (ROS) during cerebral ischemia and is more likely to lead to cell death and ultimately brain death after reperfusion. During reperfusion especially, superoxide anion free radicals, hydroxyl free radicals, and nitric oxide (NO) are produced, which can cause lipid peroxidation, inflammation and cell apoptosis. Inflammation alters the balance between pro-inflammatory and anti-inflammatory factors in cerebral ischemic injury. Inflammatory factors can therefore stimulate or exacerbate inflammation and aggravate ischemic injury. Neuroprotective therapies for various stages of the cerebral ischemia cascade response have received widespread attention. At present, neuroprotective drugs mainly include free radical scavengers, anti-inflammatory agents, and anti-apoptotic agents. However, the molecular mechanisms of the interaction between oxidative stress and inflammation, and their interplay with different types of programmed cell death in ischemia/reperfusion injury are unclear. The development of a suitable method for combination therapy has become a hot topic.

Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury.

Interleukin-10 (IL-10) is an important anti-inflammatory cytokine expressed in response to brain injury, where it facilitates the resolution of inflammatory cascades, which if prolonged causes secondary brain damage. Here, we comprehensively review the current knowledge regarding the role of IL-10 in modulating outcomes following acute brain injury, including traumatic brain injury and the various stroke subtypes. The vascular endothelium is closely tied to the pathophysiology of these neurological disorders and research has demonstrated clear vascular endothelial protective properties for IL-10. In vitro and in vivo models of ischemic stroke have convincingly directly and indirectly shown IL-10-mediated neuroprotection; although clinically, the role of IL-10 in predicting risk and outcomes is less clear. Comparatively, conclusive studies investigating the contribution of IL-10 in subarachnoid hemorrhage are lacking. Weak indirect evidence supporting the protective role of IL-10 in preclinical models of intracerebral hemorrhage exists; however, in the limited number of clinical studies, higher IL-10 levels seen post-ictus have been associated with worse outcomes. Similarly, preclinical traumatic brain injury models have suggested a neuroprotective role for IL-10; although, controversy exists among the several clinical studies. In summary, while IL-10 is consistently elevated following acute brain injury, the effect of IL-10 appears to be pathology-dependent and preclinical and clinical studies often paradoxically yield opposite results. The pronounced and potent effects of IL-10 in the resolution of inflammation and inconsistency in the literature regarding the contribution of IL-10 in the setting of acute brain injury warrant further rigorously controlled and targeted investigation.

/pdf/role-of-interleukin-10-in-acute-brain-injuries-54brammucq.pdf

Role of Interleukin-10 in Acute Brain Injuries.

Non-traumatic subarachnoid hemorrhage (SAH) affects an estimated 30,000 people each year in the United States, with an overall mortality of ~30%. Most cases of SAH result from a ruptured intracranial aneurysm, require long hospital stays, and result in significant disability and high fatality. Early brain injury (EBI) and delayed cerebral vasospasm (CV) have been implicated as leading causes of morbidity and mortality in these patients, necessitating intense focus on developing preclinical animal models that replicate clinical SAH complete with delayed CV. Despite the variety of animal models currently available, translation of findings from rodent models to clinical trials has proven especially difficult. While the explanation for this lack of translation is unclear, possibilities include the lack of standardized practices and poor replication of human pathophysiology, such as delayed cerebral vasospasm and ischemia, in rodent models of SAH. In this review, we summarize the different approaches to simulating SAH in rodents, in particular elucidating the key pathophysiology of the various methods and models. Ultimately, we suggest the development of standardized model of rodent SAH that better replicates human pathophysiology for moving forward with translational research.

/pdf/a-comparison-of-pathophysiology-in-humans-and-rodent-models-182ok4df6a.pdf

A Comparison of Pathophysiology in Humans and Rodent Models of Subarachnoid Hemorrhage.

We translated the Medication Management Ability Assessment (MMAA) from English to Spanish for use via tele-assessment and examined its reliability and validity. Following International Test Commission Guidelines for Translating and Adapting Tests, we used translation/back-translation and a small focus group (n = 6) to adapt a Spanish version of the MMAA. Eighty-six Spanish-speaking adults completed the adapted MMAA via tele-assessment at baseline and at a two-week follow-up visit. Participants also completed several self-report and performance-based cognitive and functional measures. The internal consistency of the MMAA was excellent (standardized Cronbach's α = 0.90). Performance-based functional assessments (PBFAs) and objective cognition were positively associated with the MMAA at small to medium effect sizes. Self-report measures of daily function and cognition, measures of health literacy, and estimates of premorbid intellectual functioning were not significantly associated with MMAA performance. The test-retest reliability of the MMAA was good (CCC = 0.73, 95% CI [0.62, 0.81]; rs = 0.37, p < 0.001) and demonstrated a small practice effect (Cohen's d = 0.36, p = 0.001). Preliminary evidence for the construct validity of a Spanish-language MMAA administered via tele-assessment further expands the potential clinical utility of PBFAs in culturally diverse, Spanish-speaking populations.

Evidence for the reliability and validity of a Spanish translation of the Medication Management Ability Assessment administered via tele-assessment.

The relationship between calcium oxalate kidney stone formation and inflammatory bowel disease (IBD) was first noted in two large retrospective case series from the 1960s. In over 1,400 patients with inflammatory bowel disease, 92 of 1,468 patients (6%) were identified to have developed renal stones, an occurrence that appeared as frequent as other systemic complications of this disease process [1, 2]. The mechanisms behind this high stone incidence were confirmed in the 1970s to be a complication of fat malabsorption and chronic diarrhea, which resulted in enteric hyperoxaluria, decreased urine citrate concentration and pH, and decreased urine volumes [3, 4]. Since those early descriptions, other malabsorptive intestinal disease states have also been added to the IBD/stone- associated list, including jejunoileal bypass (historical) and Roux-en-Y gastric bypass for obesity, chronic mesenteric ischemia, and small bowel ostomies [5, 6]. In general, patients with ileocolonic disease (9–17%) tend to be more commonly affected than those with ileal (6–8%) or colonic disease (3–5%) alone, and stone composition varies between calcium oxalate (malabsorptive diseases, ileocolonic Crohn’s disease) and uric acid (copious diarrhea, small bowel ostomies) depending on the disease state and amount of volume loss/diarrhea. This chapter will highlight the urinary abnormalities seen in modern bariatric surgical patients and in patients with the two most common forms of IBD (Crohn’s, ulcerative colitis) with a focus on the nutritional aspects that can be improved in these stone-forming populations.

Joshua M. Garcia

Papers

Role of Interleukin-10 in Acute Brain Injuries.

A Comparison of Pathophysiology in Humans and Rodent Models of Subarachnoid Hemorrhage.

Evidence for the reliability and validity of a Spanish translation of the Medication Management Ability Assessment administered via tele-assessment.

Malabsorptive Disorders and Inflammatory Bowel Disease: Assessing and Improving Nutritional Stone Risk

Multiple Chronic Conditions and Disability among Vietnamese Older Adults: Results from the Vietnamese Aging and Care Survey (VACS).