Here we show that conditional deletion of Pten in a subpopulation of adult neural stem cells in the subependymal zone (SEZ) leads to persistently enhanced neural stem cell self-renewal without sign of exhaustion. These Pten null SEZ-born neural stem cells and progenies can follow the endogenous migration, differentiation, and integration pathways and contribute to constitutive neurogenesis in the olfactory bulb. As a result, Pten deleted animals have increased olfactory bulb mass and enhanced olfactory function. Pten null cells in the olfactory bulb can establish normal connections with peripheral olfactory epithelium and help olfactory bulb recovery from acute damage. Following a focal stroke, Pten null progenitors give rise to greater numbers of neuroblasts that migrate to peri-infarct cortex. However, in contrast to the olfactory bulb, no significant long-term survival and integration can be observed, indicating that additional factors are necessary for long-term survival of newly born neurons after stroke. These data suggest that manipulating PTEN-controlled signaling pathways may be a useful step in facilitating endogenous neural stem/progenitor expansion for the treatment of disorders or lesions in regions associated with constitutive neurogenesis.

cannabidiolic acid (up to 55.73 mg/mL) in 13 of the 84 samples tested (15.48% [95% CI, 9.28%-24.70%]), and cannabigerol (up to 4.67 mg/mL) in 2 of the 84 samples tested (2.38% [95% CI, 0.65%-8.27%]).Discussion | Among CBD products purchased online, a wide range of CBD concentrations was found, consistent with the lack of an accepted dose. Of tested products, 26% contained less CBD than labeled, which could negate any potential clinical response. The overlabeling of CBD products in this study is similar in magnitude to levels that triggered warning letters to 14 businesses in 2015-2016 from the US Food and Drug Administration 3 (eg, actual CBD content was negligible or less than 1% of the labeled content), suggesting that there is a continued need for federal and state regulatory agencies to take steps to ensure label accuracy of these consumer products. Underlabeling is less concerning as CBD appears to neither have abuse liability nor serious adverse consequences at high doses 4,5 ; however, the THC content observed may be sufficient to produce intoxication or impairment, especially among children. 6 Although the exclusive procurement of products online is a study limitation given the frequently changing online marketplace, these products represent the most readily available to US consumers. Additional monitoring should be conducted to determine changes in this marketplace over time and to compare internet products with those sold in dispensaries. These findings highlight the need for manufacturing and testing standards, and oversight of medicinal cannabis products.

Background and Purpose-Stroke and heart disease are the most serious complications of diabetes accounting for Ͼ65% of mortality among diabetics. Although intensive insulin therapy has significantly improved the prognosis of diabetes and its complications, it is associated with an elevated risk of recurrent hypoglycemia (RH). We tested the hypothesis that RH exacerbates cerebral ischemic damage in a rodent model of diabetes. Method-We determined the extent of neuronal death in CA1 hippocampus after global cerebral ischemia in control and streptozotocin-induced diabetic rats. Diabetic animals included an insulin-treated streptozotocin-diabetic (ITD) group and a group of ITD rats exposed also to 10 episodes of hypoglycemia (ITDϩrecurrent hypoglycemia: RH). Hypoglycemia (55 to 65 mg/dL blood glucose) was induced twice daily for 5 consecutive days. Results-As expected, uncontrolled diabetes (streptozotocin-diabetes, untreated animals) resulted in a 70% increase in ischemic damage as compared with the control group. Insulin treatment was able to lower ischemic damage by 64% as compared with the diabetic group. However, ITDϩRH rats had 44% more damage when compared with the ITD group. We also observed that free radical release from mitochondria is increased in ITDϩRH rats. Conclusions-This is the first report on the impact of RH in exacerbating cerebral ischemic damage in diabetic animals.Our results suggest that increased free radical release from mitochondria may be responsible for observed increased ischemic damage in ITDϩRH rats. RH thus may be an unexplored but important factor responsible for increased ischemic damage in diabetes. (Stroke. 2011;42:1404-1411.)Key Words: brain ischemia Ⅲ cardiac arrest Ⅲ diabetes Ⅲ free radicals Ⅲ glucose Ⅲ mitochondria Ⅲ stroke D iabetes is a devastating disease of epidemic proportions. It is estimated that 220 million patients are affected by diabetes worldwide. 1 Stroke and heart disease are the most serious complications of diabetes, because they account for approximately 65% of mortality among diabetics. 2 Epidemiological studies suggest that long-term diabetes increases the risk of cerebral ischemia as well as cardiovascular disease by 2 to 4 times as compared with the nondiabetic population. [3][4][5] The incidence of cerebral ischemia is greater in patients with Type 2 diabetes mellitus than Type 1 diabetes mellitus (T1DM). 3 Furthermore, cerebral infarction after ischemia is more extensive and common in diabetics, who also display slower recovery and worse survival rates than nondiabetic subjects. 6 Animal models corroborate these clinical observations and provide mechanistic insights into the pathophysiology of the effect of diabetes on cerebral ischemia. 7,8 It has been recognized that a high plasma glucose level is a key factor for the poor outcome observed after cerebral ischemia in diabetics. 9 Attaining tight glycemic control is a desirable goal for both patients with T1DM and Type 2 diabetes mellitus. Aggressive therapeutic interventions able to normalize glycohemog...

Purpose: Colon cancer is one of the most common human malignancies, yet studies have only begun to identify the multiple mechanisms that underlie the development of this tumor. In this study, we have identified a novel mechanism, dysregulation of endocytic sorting, which promotes colon cancer development. Experimental Design: Immunohistochemical and microarray analyses were done on human colon cancer tissue specimens to determine the levels of one endocytic protein, sorting nexin 1 (SNX1). SW480 cells, a human colon cancer cell line that retains a relatively high level of SNX1 expression, were used to assess the effects of down-regulating this protein by small hairpin RNA. Activation of signal transduction cascades was evaluated in these cells using Western blotting, and multiple functional assays were done. Results: We determined by immunohistochemistry that the level of SNX1 was significantly down-regulated in 75% of human colon cancers. In corroborative studies using microarray analysis, SNX1 message was significantly decreased (log 2 ratio less than À1) for 8 of 19 colon carcinomas. Cell lines with reduced SNX1 levels showed increased proliferation, decreased apoptosis, and decreased susceptibility to anoikis. They also showed increased activation of epidermal growth factor receptor and extracellular signal-regulated kinase 1/2 in response to epidermal growth factor. This increased activation was abolished by inhibition of endocytosis. Conclusions: These data suggest that loss of SNX1 may play a significant role in the development and aggressiveness of human colon cancer, at least partially through the mechanism of increased signaling from endosomes. Further, these findings suggest that dysregulation of endocytic proteins may represent a new paradigm in the process of carcinogenesis.