Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer's Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that presently affects an estimated 5.7 million Americans. Understanding the basis for this disease is key for the development of a future successful treatment. In this effort, we previously reported that mouse prion protein-promoter-driven, ubiquitous expression of familial AD (FAD)-linked human PSEN1 variants in transgenic mice impairs environmental enrichment (EE)-induced proliferation and neurogenesis of adult hippocampal neural progenitor cells (AHNPCs) and in a non-cell autonomous manner. These findings were confirmed in PS1M146V/+ mice that harbor an FAD-linked mutation in the endogenous PSEN1 gene. We now demonstrate that CSF1R antagonist-mediated microglial depletion in transgenic male mice expressing mutant presenilin 1 (PS1) or PS1M146V/+ "knock-in" mice leads to a complete rescue of deficits in proliferation, differentiation and survival of AHNPCs. Moreover, microglia depletion suppressed the heightened baseline anxiety behavior observed in transgenic mice expressing mutant PS1 and PS1M146V/+ mice to levels observed in mice expressing wild-type human PS1 or nontransgenic mice, respectively. These findings demonstrate that in mice expressing FAD-linked PS1, microglia play a critical role in the regulation of EE-dependent AHNPC proliferation and neurogenesis and the modulation of affective behaviors.SIGNIFICANCE STATEMENT Inheritance of mutations in genes encoding presenilin 1 (PS1) causes familial Alzheimer's disease (FAD). Mutant PS1 expression enhances the levels and assembly of toxic Aß42 peptides and impairs the self-renewal and neuronal differentiation of adult hippocampal neural progenitor cells (AHNPCs) following environmental enrichment (EE) that is associated with heightened baseline anxiety. We now show that microglial depletion fully restores the EE-mediated impairments in AHNPC phenotypes and suppresses the heightened baseline anxiety observed in mice expressing FAD-linked PS1. Thus, we conclude that the memory deficits and anxiety-related behaviors in patients with PS1 mutations is a reflection not just of an increase in the levels of Aß42 peptides, but to impairments in the self-renewal and neuronal differentiation of AHNPCs that modulate affective behaviors.

School Factors and Alcohol Use: The Moderating Effect of Nativity in a National Sample of Latino Adolescents.

BACKGROUND: School is an important developmental context for adolescents and may be related to adolescent alcohol use. Less is known as to whether the relationships between school factors and alcohol use differ between Latino youth born outside of the United States versus those born in the United States. OBJECTIVE: The aim of this study is to test nativity as a moderator of the relationship between school factors and alcohol use among Latino adolescents. METHODS: This study used data from Waves I and II of the National Longitudinal Study of Adolescent Health (Add Health) to test nativity as a moderator of the relationship between school factors and alcohol use in a subsample of Latino adolescents. RESULTS: Results found that during adolescence, nativity moderates the relationship between school connectedness and Wave I alcohol use. For those born outside of the United States, school connectedness was not related to alcohol use. Significant main effects emerged for grades in school and truancy. Better grades were associated with less alcohol use, while truancy was associated with greater alcohol use. The longitudinal relationships between school factors and Wave II alcohol use were not statistically significant. CONCLUSIONS: School connectedness is a contemporaneous risk factor for alcohol use among those born in the United States. Prevention efforts that address school contextual factors may be important for all Latino students to reduce engagement in alcohol use and optimize well-being.

Glycine N-methyltransferase expression in the hippocampus and its role in neurogenesis and cognitive performance.

The hippocampus is a brain area characterized by its high plasticity, observed at all levels of organization: molecular, synaptic, and cellular, the latter referring to the capacity of neural precursors within the hippocampus to give rise to new neurons throughout life. Recent findings suggest that promoter methylation is a plastic process subjected to regulation, and this plasticity seems to be particularly important for hippocampal neurogenesis. We have detected the enzyme GNMT (a liver metabolic enzyme) in the hippocampus. GNMT regulates intracellular levels of SAMe, which is a universal methyl donor implied in almost all methylation reactions and, thus, of prime importance for DNA methylation. In addition, we show that deficiency of this enzyme in mice (Gnmt-/-) results in high SAMe levels within the hippocampus, reduced neurogenic capacity, and spatial learning and memory impairment. In vitro, SAMe inhibited neural precursor cell division in a concentration-dependent manner, but only when proliferation signals were triggered by bFGF. Indeed, SAMe inhibited the bFGF-stimulated MAP kinase signaling cascade, resulting in decreased cyclin E expression. These results suggest that alterations in the concentration of SAMe impair neurogenesis and contribute to cognitive decline.

Template for a program tailored ACS/APDS phase 1 curriculum: From needs assessment to implementation.

BACKGROUND: The Phase 1 ACS/APDS skills curriculum standardizes intern training. Despite this, institutional implementation varies and is nationally low. We aimed to use Kern's six-steps to tailor this to our program, providing a framework to improve implementation. METHODS: Problem identification and general needs assessment were performed. Targeted needs assessment (TNA) of incoming interns ('interns'), current residents, and attendings determined perceived importance of skills and intern's previous experience and confidence. Educational strategies were developed. Learner knowledge was assessed before and after modules, deficiencies identified enabled employment of active learning strategies. Modular and curricular evaluations were completed. RESULTS: TNA determined all interns had been taught knot tying and suturing, and were most confident with suturing, knot tying, and urethral catheterization. Educational strategies included simulation and lectures. Evaluations demonstrated improvement in test scores (pre-v post-) and skills confidence on curricula completion. CONCLUSION: Our framework utilizes institutional resources and expertise while focusing on determining existing knowledge, skill, and technical deficiencies of learners. This approach demonstrated improvement in knowledge and confidence, and could improve implementation rates of the Phase 1 curriculum.

Simultaneous Monitoring of Wireless Electrophysiology and Memory Behavioral Test as a Tool to Study Hippocampal Neurogenesis.

Brainwaves amplitude obtained from electroencephalography (EEG) has been well-recognized as a basis for cognitive capacity, memory, and learning on animals and humans. Adult neurogenesis mechanism is also linked to memory and learning improvement. Traditionally, researchers used to assess learning and memory parameters in rodent models by behavioral tasks. Therefore, the simultaneous monitoring of behavioral changes and EEG is particularly interesting in correlating data between brain activity and task-related behaviors. However, most of the equipment required to perform both studies are either complex, expensive, or uses a wired setup network that hinders the natural animals' movement. In this study, EEG was recorded with a wireless electrophysiology device along with the execution of a novel object recognition task (NORT). The animal's behavior was monitored simultaneously by a video tracking system. Both recordings were analyzed offline by their timestamps which were synched to link EEG signals with the animal's actions. Subjects consist of adult Wistar rats after medium-term environmental enrichment treatment. Six skull screw electrodes were fixed in pairs on both hemispheres over frontal, central, and parietal regions and were referenced to an electrode located posterior of the nasal bone. NORT protocol consists of exposing the animal to two identical objects for 10 min. After 2 h and 24 h, one of the objects was replaced with a novel one. Exploration time for each object was monitored by a behavioral tracking software (BTS) and EEG data recording. The analysis of the EEG synced with behavioral data consists of estimations of alpha and beta relative band power and comparisons between novel object recognition versus familiar object exploration, between three experimental stages. In this manuscript, we have discussed electrodes manufacturing process, epidural electrodes implantation surgery, environmental enrichment protocol, NORT protocol, BTS setup, EEG - BTS coupling for simultaneous monitoring in real-time, and EEG data analysis based on automatic events detection.

Beneficial effects of Japanese sake yeast supplement on biochemical, antioxidant, and anti-inflammatory factors in streptozotocin-induced diabetic rats.

BACKGROUND: Using chemical agents in the treatment of diabetes mellitus type 2 may have some limitations due to frequent side effects. Some novel and natural agents may be promising alternatives in this case. This study was designed to evaluate the effects of oral Japanese sake yeast supplement, as a novel agent, on biochemical antioxidant and anti-inflammatory parameters in experimentally induced diabetic rats. MATERIALS AND METHODS: After inducing diabetes (55 mg/kg intraperitoneal injection of streptozotocin), 120 male adult Wistar rats were randomly divided into 5 groups and each group received 0 (control), 15, 30, or 45 mg/kg of sake yeast or was considered a nondiabetic control. Then, the serum levels of tumor necrosis factor-α, IL-6, C-reactive protein, malondialdehyde, glutathione, total antioxidant status, glucose, cholesterol, triglycerides, and insulin were evaluated and compared to baseline measures. RESULTS: The results showed that oral administration of sake yeast at different concentrations reduced levels of malondialdehyde, glucose, cholesterol, and triglycerides and increased levels of insulin, glutathione, and total antioxidants (P<0.05). The best responses were observed in the nondiabetic control group. CONCLUSION: Sake yeast supplement may be useful as a novel agent in the treatment of diabetes.

Clinical outcomes of pancreaticoduodenectomy in octogenarians: a surgeon's experience from 2007 to 2015.

BACKGROUND: As the number of elderly people in our population increases, there will be a greater number of octogenarians who will need pancreaticoduodenectomy as the only curative option for periampullary malignancies. This study evaluated clinical outcomes of pancreaticoduodenectomy in octogenarians, in comparison to younger patients. METHODS: A retrospective review was conducted of 216 consecutive patients who underwent pancreaticoduodenectomy from January 2007 to April 2015. A two-sided Fisher's exact statistical analysis was used to compare pre-operative comorbidities, intra-operative factors, surgical pathology, and post-operative complication rates between non-octogenarians and octogenarians. RESULTS: One hundred and eighty three non-octogenarians and 33 octogenarians underwent pancreaticoduodenectomy. Of patients with periampullary adenocarcinoma, octogenarians were more likely to present with advanced disease state (P=0.01). The two cohorts had similar ASA scores (P=0.62); however, octogenarians were more likely to have coronary artery disease (P=0.03). The length of operation was shorter in octogenarians (P=0.002). Mortality rates (P=0.49) and overall postoperative complication rates (P=1.0) were similar in two cohorts; however octogenarians had a higher incidence of pulmonary embolism (P=0.02). CONCLUSIONS: Our data demonstrates that octogenarians can undergo pancreaticoduodenectomy with outcomes similar to those in younger patients. Thus, patients should not be denied a curative surgical option for periampullary malignancy based on advanced age alone.

The Use of NPWT-i Technology in Complex Surgical Wounds.

Advanced wound management of complex surgical wounds remains a significant challenge as more patients are being hospitalized with infected wounds. Reducing recurrent infections and promoting granulation tissue formation is essential to overall wound healing. Wounds with acute infection and critical colonization require advanced multimodal approaches including systemic antibiotics, surgical debridement, and primary wound care. The goal in surgical wound management is to optimize clinical outcomes such as time to wound closure and functional recovery. A review of current literature suggests that negative pressure wound therapy with instillation (NPWT-i) is a viable adjunct therapy in the management of infected wounds especially in patients with medical comorbidities. The aim of this case series is to highlight the ability of NPWT-i as adjunct to prepare the wound bed for closure on infected surgical wounds that would normally require multiple operations to obtain source control.

A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis.

Adult neurogenesis is the process by which new neurons are generated in the brains of adults. Since its discovery 50 years ago, adult neurogenesis has been widely studied in the mammalian brain and has provided a new perspective on the pathophysiology of many psychiatric and neurodegenerative disorders, some of which affect memory. In this regard, adult hippocampal neurogenesis (AHN), which occurs in the subgranular zone (SGZ) of the dentate gyrus (DG), has been suggested to play a role in the formation and consolidation of new memories. This process involves many transcription factors, of which cyclic AMP (cAMP)-responsive element-binding protein (CREB) is a well-documented one. In the developing brain, CREB regulates crucial cell stages (e.g., proliferation, differentiation, and survival), and in the adult brain, it participates in neuronal plasticity, learning, and memory. In addition, new evidence supports the hypothesis that CREB may also participate in learning and memory through its involvement in AHN. This review examines the CREB family of transcription factors, including the different members and known signaling pathways. It highlights the role of CREB as a modulator of AHN, which could underlie its function in memory consolidation mechanisms.

Influences of prenatal and postnatal stress on adult hippocampal neurogenesis: the double neurogenic niche hypothesis.

Adult hippocampal neurogenesis (AHN) is involved in learning, memory, and stress, and plays a significant role in neurodegenerative and psychiatric disorders. As an age-dependent process, AHN is largely influenced by changes that occur during the pre- and postnatal stages of brain development, and constitutes an important field of research. This review examines the current knowledge regarding the regulators of AHN and the influence of prenatal and postnatal stress on later AHN. In addition, a hypothesis is presented suggesting that each kind of stress influences a specific neurogenic pool, developmental or postnatal, that later becomes a precursor with important repercussions for AHN. This hypothesis is referred to as "the double neurogenic niche hypothesis." Discovering what receptors, transcription factors, or genes are specifically activated by different stressors is proposed as an essential line of future research in the field. Such knowledge shall constitute an important starting point toward the goal of modifying AHN in neurodegenerative or psychiatric diseases.

Dexamethasone acts as a radiosensitizer in three astrocytoma cell lines via oxidative stress.

Glucocorticoids (GCs), which act on stress pathways, are well-established in the co-treatment of different kinds of tumors; however, the underlying mechanisms by which GCs act are not yet well elucidated. As such, this work investigates the role of glucocorticoids, specifically dexamethasone (DEXA), in the processes referred to as DNA damage and DNA damage response (DDR), establishing a new approach in three astrocytomas cell lines (CT2A, APP.PS1 L.1 and APP.PS1 L.3). The results show that DEXA administration increased the basal levels of gamma-H2AX foci, keeping them higher 4h after irradiation (IR) of the cells, compared to untreated cells. This means that DEXA might cause increased radiosensitivity in these cell lines. On the other hand, DEXA did not have an apparent effect on the formation and disappearance of the 53BP1 foci. Furthermore, it was found that DEXA administered 2h before IR led to a radical change in DNA repair kinetics, even DEXA does not affect cell cycle. It is important to highlight that DEXA produced cell death in these cell lines compared to untreated cells. Finally and most important, the high levels of gamma-H2AX could be reversed by administration of ascorbic acid, a potent blocker of reactive oxygen species, suggesting that DEXA acts by causing DNA damage via oxidative stress. These exiting findings suggest that DEXA might promote radiosensitivity in brain tumors, specifically in astrocytoma-like tumors.

Bypass grafting between the supraceliac aorta and the common hepatic artery during pancreaticoduodenectomy.

Patients with celiac artery stenosis often remain asymptomatic due to formation of extensive collateral pathways. Hepatic or anastomotic ischemia may occur when the gastroduodenal artery and these collaterals are ligated during pancreaticoduodenectomy. Here, we present a patient with severe atherosclerotic disease of the celiac axis who successfully underwent pancreaticoduodenectomy with aorto-hepatic bypass.

The postnatal origin of adult neural stem cells and the effects of glucocorticoids on their genesis.

The relevance of adult neurogenesis in hippocampal function is well documented, as is the potential impact stress has on the adult neurogenic niche. Adult born neurons are generated from neural precursors in the dentate gyrus (DG), although the point in postnatal development that these cell precursors originate is not known. This is particularly relevant if we consider the effects stress may have on the development of neural precursors, and whether such effects on adult neurogenesis and behavior may persist in the long-term. We have analyzed the proportion of neural precursors in the adult murine hippocampus born on specific days during postnatal development using a dual birth-dating analysis, and we assessed their sensitivity to dexamethasone (DEX) on the peak day of cell generation. We also studied the consequences of postnatal DEX administration on adult hippocampal-dependent behavior. Postnatal day 6 (P6) is a preferred period for proliferating neural stem cells (NSCs) to become the precursors that remain in a proliferative state throughout adulthood. This window is independent of gender, the cell's location in the DG granule cell layer or their rostro-caudal position. DEX administration at P6 reduces the size of the adult NSC pool in the DG, which is correlated with poor learning/memory capacity and increased anxiety-like behavior. These results indicate that aNSCs are generated non-uniformly during postnatal development, with peak generation on day P6, and that stress receptor activation during the key period of postnatal NSC generation has a profound impact on both adult hippocampal neurogenesis and behavior.

BRCA1 loss activates cathepsin L-mediated degradation of 53BP1 in breast cancer cells.

Loss of 53BP1 rescues BRCA1 deficiency and is associated with BRCA1-deficient and triple-negative breast cancers (TNBC) and with resistance to genotoxic drugs. The mechanisms responsible for decreased 53BP1 transcript and protein levels in tumors remain unknown. Here, we demonstrate that BRCA1 loss activates cathepsin L (CTSL)-mediated degradation of 53BP1. Activation of this pathway rescued homologous recombination repair and allowed BRCA1-deficient cells to bypass growth arrest. Importantly, depletion or inhibition of CTSL with vitamin D or specific inhibitors stabilized 53BP1 and increased genomic instability in response to radiation and poly(adenosine diphosphate-ribose) polymerase inhibitors, compromising proliferation. Analysis of human breast tumors identified nuclear CTSL as a positive biomarker for TNBC, which correlated inversely with 53BP1. Importantly, nuclear levels of CTSL, vitamin D receptor, and 53BP1 emerged as a novel triple biomarker signature for stratification of patients with BRCA1-mutated tumors and TNBC, with potential predictive value for drug response. We identify here a novel pathway with prospective relevance for diagnosis and customization of breast cancer therapy.