bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ablation of Newly Generated Hippocampal Granule Cells Has Disease-Modifying Effects in Epilepsy
Authors: Hosford Bethany E. , Liska John P. , Danzer Steve C. 
Published: October 2016

Hippocampal granule cells generated in the weeks before and after an epileptogenic brain injury can integrate abnormally into the dentate gyrus, potentially mediating temporal lobe epileptogenesis. Previous studies have demonstrated that inhibiting granule cell production before an epileptogenic brain insult can mitigate epileptogenesis. Here, we extend upon these findings by ablating newly generated cells after the epileptogenic insult using a conditional, inducible diphtheria-toxin receptor expression strategy in mice. Diphtheria-toxin receptor expression was induced among granule cells born up to 5 weeks before pilocarpine-induced status epilepticus and these cells were then eliminated beginning 3 d after the epileptogenic injury. This treatment produced a 50% reduction in seizure frequency, but also a 20% increase in seizure duration, when the animals were examined 2 months later. These findings provide the first proof-of-concept data demonstrating that granule cell ablation therapy applied at a clinically relevant time point after injury can have disease-modifying effects in epilepsy.SIGNIFICANCE STATEMENTThese findings support the long-standing hypothesis that newly generated dentate granule cells are pro-epileptogenic and contribute to the occurrence of seizures. This work also provides the first evidence that ablation of newly generated granule cells can be an effective therapy when begun at a clinically relevant time point after an epileptogenic insult. The present study also demonstrates that granule cell ablation, while reducing seizure frequency, paradoxically increases seizure duration. This paradoxical effect may reflect a disruption of homeostatic mechanisms that normally act to reduce seizure duration, but only when seizures occur frequently.
Uric Acid Induces Cognitive Dysfunction through Hippocampal Inflammation in Rodents and Humans
Authors: Shao Xiaoni , Lu Wenjie , Gao Fabao , Li Dandan , Hu Jing , Li Yan , Zuo Zeping , Jie Hui , Zhao Yinglan , Cen Xiaobo 
Published: October 2016

Uric acid (UA) is a purine metabolite that in most mammals is degraded by the hepatic enzyme uricase to allantoin. Epidemiological studies have shown that an elevated UA level predicts the development of cognition and memory deficits; however, there is no direct evidence of this relationship, and the underlying mechanism is largely undefined. Here, we show that a high-UA diet triggers the expression of proinflammatory cytokines, activates the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway, and increases gliosis in the hippocampus of Wistar rats. We, subsequently, identify a specific inhibitor of NF-κB, BAY11-7085, and show that stereotactic injections of the inhibitor markedly ameliorate UA-induced hippocampal inflammation and memory deficits in C57BL/6 mice. We also found that NF-κB is activated in the primary cultured hippocampal cells after UA administration. Additionally, C57BL/6 mice that lack TLR4 are substantially protected against UA-induced cognitive dysfunction, possibly due to a decrease in inflammatory gene expression in the hippocampus. Importantly, magnetic resonance imaging confirms that hyperuricemia in rats and humans is associated with gliosis in the hippocampus. Together, these results suggest that UA can cause hippocampal inflammation via the TLR4/NF-κB pathway, resulting in cognitive dysfunction. Our findings provide a potential therapeutic strategy for counteracting UA-induced neurodegeneration.SIGNIFICANCE STATEMENTThis work demonstrates that a high-uric acid (UA) diet triggers the expression of proinflammatory cytokines, activates the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway, and increases gliosis in the hippocampus of Wistar rats. Inhibition of the NF-κB signaling pathway markedly ameliorates UA-induced hippocampal inflammation and cognitive dysfunction in C57BL/6 mice. TLR4-knock-out mice are substantially protected against UA-induced cognitive dysfunction, possibly due to a decrease in inflammatory gene expression in the hippocampus. Moreover, magnetic resonance imaging confirms that hyperuricemia in rats and humans are associated with gliosis in the hippocampus. Together, this study suggests that there is an important link between UA-induced cognitive dysfunction and hippocampal inflammation in rodents and humans, which may have remarkable implications in the treatment of UA-induced neurodegeneration.
Light-Driven Processes Control Both Rhodopsin Maturation and Recycling in Mosquito Photoreceptors
Authors: Metoxen Alexander J. , Leming Matthew T. , Hu Xiaobang , Whaley Michelle A. , O'Tousa Joseph E. 
Published: October 2016

Many invertebrates carry out a daily cycle of shedding and rebuilding of the photoreceptor's photosensitive rhabdomeric membranes. The mosquitoAedes aegyptishows a robust response, losing nearly all Aaop1 rhodopsin from the rhabdomeric membranes during the shedding process at dawn. Here, we made use of Aaop1 antibodies capable of distinguishing newly synthesized, glycosylated rhodopsin from mature nonglycosylated rhodopsin to characterize the fate of Aaop1 during the shedding and rebuilding processes. The rhabdomeric rhodopsin is moved into large cytoplasmic vesicles at dawn and is subsequently degraded during the standard 12 h daytime period. The endocytosed rhodopsin is trafficked back to the photosensitive membranes if animals are shifted back to dark conditions during the morning hours. During the daytime period, small vesicles containing newly synthesized and glycosylated Aaop1 rhodopsin accumulate within the cytoplasm. At dusk, these vesicles are lost as the newly synthesized Aaop1 is converted to the nonglycosylated form and deposited in the rhabdomeres. We demonstrate that light acts though a novel signaling pathway to block rhodopsin maturation, thus inhibiting the deglycosylation and rhabdomeric targeting of newly synthesized Aaop1 rhodopsin. Therefore, light controls two cellular processes responsible for the daily renewal of rhodopsin: rhodopsin endocytosis at dawn and inhibition of rhodopsin maturation until dusk.SIGNIFICANCE STATEMENTOrganisms use multiple strategies to maximize visual capabilities in different light conditions. Many invertebrates show a daily cycle of shedding the photoreceptor's rhabdomeric membranes at dawn and rebuilding these during the following night. We show here that theAedes aegyptimosquito possesses two distinct light-driven cellular signaling processes for modulating rhodopsin content during this cycle. One of these, endocytosis of rhabdomeric rhodopsin, has been described previously. The second, a light-activated cellular pathway acting to inhibit the anterograde movement of newly synthesized rhodopsin, is revealed here for the first time. The discovery of this cellular signaling pathway controlling a G-protein-coupled receptor is of broad interest due to the prominent role of this receptor family across all areas of neuroscience.
Differential Expression of Munc13-2 Produces Unique Synaptic Phenotypes in the Basolateral Amygdala of C57BL/6J and DBA/2J Mice
Authors: Gioia Dominic A. , Alexander Nancy J. , McCool Brian A. 
Published: October 2016

C57BL/6J (B6) and DBA/2J (D2) mice are well known to differentially express a number of behavioral phenotypes, including anxiety-like behavior, fear conditioning, and drug self-administration. However, the cellular mechanisms contributing to these differences remain unclear. Given the basolateral amygdala (BLA) contributes to these behaviors, we characterized strain-dependent differences in presynaptic and postsynaptic function in BLA neurons by integrating electrophysiological, biochemical, and genetic approaches to identify specific molecular mechanisms. We found that D2 glutamatergic synapses expressed enhanced release probability and lower sensitivity to both the inhibitory effects of low extracellular calcium and facilitation by phorbol esters. Furthermore, repetitive stimulation of BLA afferents at low (2 Hz) or high (40 Hz) frequencies revealed that B6 terminals, relative to D2 terminals, were more sensitive to synaptic fatigue principally because of reduced vesicle recycling rates. Additionally, B6 synapses exhibited more robust augmentation of spontaneous release after repetitive stimulation relative to the D2 strain.In silicoanalysis of the inheritance of synaptic physiology from an array of BXD recombinant inbred strains (Jansen et al., 2011) identified a segment on chromosome 4 containing the gene encoding Munc13-2, which has calcium-/phorbol ester-binding domains and controls presynaptic function. We subsequently found that B6 mice express substantially higher levels of Munc13-2 compared with the D2 strain whereas expression of several release-related proteins, including Munc13-1, was equivalent. We then knocked down the expression of Munc13-2 in B6 mice using a short hairpin RNA and found this recapitulated the presynaptic phenotype of D2 BLA synapses.SIGNIFICANCE STATEMENTDBA/2J and C57BL/6J mice have been used to understand the genetic mechanisms controlling behaviors related to a number of psychiatric illnesses. However, the fundamental neurobiological mechanisms producing these behavioral characteristics remain unresolved. Here we identify a critical family of presynaptic proteins differentially expressed by these strains that control strain-dependent synaptic physiology. This family of proteins regulates excitation/secretion coupling, vesicle recycling, and short-term plasticity throughout the CNS. Thus, differential inheritance of proteins like Munc13-2 has broad implications for genetic control over a wide variety of pathological behaviors. Importantly, these proteins also contain a large number of modulatory sites, making them attractive potential targets for the development of novel neuropharmaceutical treatments.
Oxidation of KCNB1 Potassium Channels Causes Neurotoxicity and Cognitive Impairment in a Mouse Model of Traumatic Brain Injury
Authors: Yu Wei , Parakramaweera Randika , Teng Shavonne , Gowda Manasa , Sharad Yashsavi , Thakker-Varia Smita , Alder Janet , Sesti Federico 
Published: October 2016

The delayed rectifier potassium (K+) channel KCNB1 (Kv2.1), which conducts a major somatodendritic current in cortex and hippocampus, is known to undergo oxidation in the brain, but whether this can cause neurodegeneration and cognitive impairment is not known. Here, we used transgenic mice harboring human KCNB1 wild-type (Tg-WT) or a nonoxidable C73A mutant (Tg-C73A) in cortex and hippocampus to determine whether oxidized KCNB1 channels affect brain function. Animals were subjected to moderate traumatic brain injury (TBI), a condition characterized by extensive oxidative stress. Dasatinib, a Food and Drug Administration–approved inhibitor of Src tyrosine kinases, was used to impinge on the proapoptotic signaling pathway activated by oxidized KCNB1 channels. Thus, typical lesions of brain injury, namely, inflammation (astrocytosis), neurodegeneration, and cell death, were markedly reduced in Tg-C73A and dasatinib-treated non-Tg animals. Accordingly, Tg-C73A mice and non-Tg mice treated with dasatinib exhibited improved behavioral outcomes in motor (rotarod) and cognitive (Morris water maze) assays compared to controls. Moreover, the activity of Src kinases, along with oxidative stress, were significantly diminished in Tg-C73A brains. Together, these data demonstrate that oxidation of KCNB1 channels is a contributing mechanism to cellular and behavioral deficits in vertebrates and suggest a new therapeutic approach to TBI.SIGNIFICANCE STATEMENTThis study provides the first experimental evidence that oxidation of a K+channel constitutes a mechanism of neuronal and cognitive impairment in vertebrates. Specifically, the interaction of KCNB1 channels with reactive oxygen species plays a major role in the etiology of mouse model of traumatic brain injury (TBI), a condition associated with extensive oxidative stress. In addition, a Food and Drug Administration–approved drug ameliorates the outcome of TBI in mouse, by directly impinging on the toxic pathway activated in response to oxidation of the KCNB1 channel. These findings elucidate a basic mechanism of neurotoxicity in vertebrates and might lead to a new therapeutic approach to TBI in humans, which, despite significant efforts, is a condition that remains without effective pharmacological treatments.
The Rubber Tail Illusion as Evidence of Body Ownership in Mice
Authors: Wada Makoto , Takano Kouji , Ora Hiroki , Ide Masakazu , Kansaku Kenji 
Published: October 2016

The ownership of one's body parts represents a fundamental aspect of self-consciousness. Accumulating empirical evidence supports the existence of this concept in humans and nonhuman primates, but it is unclear whether nonprimate mammals experience similar feelings. Therefore, the present study used rubber tails to investigate body ownership in rodents. When the real tails and rubber tails were synchronously stroked, the mice responded as if their own tails were touched when the rubber tails were grasped. In contrast, when the stimuli were delivered asynchronously, there was a significantly lower mean response rate when the rubber tail was grasped. These findings suggest that mice may experience body ownership of their tails, suggestive of the rubber hand illusion in humans.SIGNIFICANCE STATEMENTTo explore the manner in which the ownership of body parts is experienced, this study specifically used the rubber hand illusion (RHI), in which self-consciousness can be extended out of one's own body. Accumulating empirical evidence supports the existence of this concept in humans and nonhuman primates, but it remains unclear whether nonprimate mammals experience similar feelings. This study demonstrated for the first time that mice may experience body ownership of their tails, which is suggestive of the RHI in humans and provides evidence that may highlight how humans experience the ownership of body parts.
CD8+T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain
Authors: Krukowski Karen , Eijkelkamp Niels , Laumet Geoffroy , Hack C. Erik , Li Yan , Dougherty Patrick M. , Heijnen Cobi J. , Kavelaars Annemieke 
Published: October 2016

Chemotherapy-induced peripheral neuropathy (CIPN), characterized by pain and numbness in hands and feet, is a common side effect of cancer treatment. In most patients, symptoms of CIPN subside after treatment completion. However, in a substantial subgroup, CIPN persists long into survivorship. Impairment in pain resolution pathways may explain persistent CIPN. We investigated the contribution of T cells and endogenous interleukin (IL)-10 to resolution of CIPN. Paclitaxel-induced mechanical allodynia was prolonged in T-cell-deficient (Rag1−/−) mice compared with wild-type (WT) mice. There were no differences between WT and Rag1−/−mice in severity of paclitaxel-induced mechanical allodynia. Adoptive transfer of either CD3+or CD8+, but not CD4+, T cells to Rag1−/−mice normalized resolution of CIPN. Paclitaxel treatment increased the number of T cells in lumbar dorsal root ganglia (DRG), where CD8+T cells were the major subset. Inhibition of endogenous IL-10 signaling by intrathecal injection of anti-IL-10 to WT mice or Rag1−/−mice reconstituted with CD8+T cells delayed recovery from paclitaxel-induced mechanical allodynia. Recovery was also delayed in IL-10 knock-out mice. Conversely, administration of exogenous IL-10 attenuated paclitaxel-induced allodynia.In vitro, IL-10 suppressed abnormal paclitaxel-induced spontaneous discharges in DRG neurons. Paclitaxel increased DRG IL-10 receptor expression and this effect requires CD8+T cells. In conclusion, we identified a novel mechanism for resolution of CIPN that requires CD8+T cells and endogenous IL-10. We propose that CD8+T cells increase DRG IL-10 receptor expression and that IL-10 suppresses the abnormal paclitaxel-induced spontaneous discharges by DRG neurons to promote recovery from CIPN.SIGNIFICANCE STATEMENTChemotherapy-induced peripheral neuropathy persists after completion of cancer treatment in a significant subset of patients, whereas others recover. Persistent neuropathy after completion of cancer treatment severely affects quality of life. We propose that understanding how neuropathy resolves will identify novel avenues for treatment. We identified a novel and critical role for CD8+T cells and for endogenous IL-10 in recovery from paclitaxel-induced neuropathy in mice. Enhancing the capacity of CD8+T cells to promote resolution or increasing IL-10 signaling are promising targets for novel interventions. Clinically, peripheral blood CD8+T-cell function and/or the capacity of individuals to produce IL-10 may represent biomarkers of risk for developing persistent peripheral neuropathy after completion of cancer treatment.
Are Care Plans Suitable for the Management of Multiple Conditions?
Authors: Young Charlotte E. , Boyle Frances M. , Mutch Allyson J. 
Published: October 2016

Background Care plans have been part of the primary care landscape in Australia for almost two decades. With an increasing number of patients presenting with multiple chronic conditions, it is timely to consider whether care plans meet the needs of patients and clinicians. Objectives To review and benchmark existing care plan templates that include recommendations for comorbid conditions, against four key criteria: (i) patient preferences, (ii) setting priorities, (iii) identifying conflicts and synergies between conditions, and (iv) setting dates for reviewing the care plan. Design Document analysis of Australian care plan templates published from 2006 to 2014 that incorporated recommendations for managing comorbid conditions in primary care. Results Sixteen templates were reviewed. All of the care plan templates addressed patient preference, but this was not done comprehensively. Only three templates included setting priorities. None assisted in identifying conflicts and synergies between conditions. Fifteen templates included setting a date for reviewing the care plan. Conclusions Care plans are a well-used tool in primary care practice, but their current format perpetuates a single-disease approach to care, which works contrary to their intended purpose. Restructuring care plans to incorporate shared decision-making and attention to patient preferences may assist in shifting the focus back to the patient and their care needs.
Multidetector computer tomography with virtual bronchoscopy for diagnosis of trachea neoplasms
Authors: Kotlyarov P. M. 
Published: October 2016

The aim of this study was to estimate diagnostic value of virtual bronchoscopy (VB) in patients with trachea neoplasms.Methods. Results of multidetector computed tomography with virtual bronchoscopy (MDCT"VB) were analyzed in 31 patients with neoplastic lesions of the trachea according to an original method developed in our institution.Results. The method allowed complete evaluation of location and extension of tumors, differentiation between benign and malignant tumors including those complicated by stenosis precluded from bronchoscopic examination. A sessile tumor with destructed underlying tissue, a rough surface, infiltrated tracheal wall, tumor extension outside the trachea, and infiltration of the mediastinum were considered as malignant signs. Similar signs were seen in metastatic lesions of the trachea from lung carcinoma: the carina and the distal trachea were injured if the tumor grew from a main bronchus, a tracheal wall was injured if a lung tumor penetrated the mediastinum.Conclusion. MDCT"VB appears to be the optimal diagnostic method in tumors of the trachea. In cases of trachea stenosis, MDCT"VB is the preferable method for evaluation of the tumor extension. Virtual modeling of an intratracheal tumor could help to make a decision about radical treatment.
Association between intracardiac hemodynamics and respiratory function in patients with coronary artery disease and respiratory comorbidity
Authors: Bazdyrev E. D. , Polikutina O. M. , Kalichenko N. A. , Slepynina Yu. S. , Pavlova V. Yu. , Barbarash O. I. 
Published: October 2016

The aim of this study was to investigate a relationship between the myocardial structure and function and respiratory parameters in patients with coronary artery disease (CAD) and respiratory disease.Methods. We performed spirometry, body plethysmography, lung diffusing capacity test and measured the left ventricle (LV) systolic and diastolic function in patients with CAD with or without respiratory diseases and ventilation disorders.Results. Patients with CAD (n = 662) participated in the study. The LV systolic dysfunction was found only in 60 patients (9.1%), while diastolic dysfunction was found in 387 patients with CAD (58.4%). Most patients with obstructive ventilation disorders had the systolic or diastolic LV dysfunction (40 patients (66.7%) and 197 patients (79.4%), respectively). Flow and volume lung function parameters and the lung diffusing capacity were associated with some echocardiographic and pulsed wave Doppler parameters.Conclusion. Comorbidity of CAD and lung obstructive disease was associated with more frequent systolic and diastolic LV dysfunction. The relationship between respiratory and cardiac parameters could indicate the cross impact that could deteriorate the course of both the diseases.
Perspective investigations of empyema pathogenesis
Authors: Kosareva P. V. , Khorinko A. V. , Amarantov D. G. 
Published: October 2016

Pleural empyema is one of the most serious septic diseases. Despite favorable outcome, therapeutic and prognostic strategies in empyema are needed to be improved. Further investigation of pathology and diagnostic histological criteria of acute and chronic purulent pleural inflammation and fibrosis is a perspective research direction, as morphological characteristics are important for prognosis and the optimal treatment choice. However, complete histological examination of the lung tissue and the visceral pleura is difficult in real clinical practice, because any lung damage can cause bronchial fistula. Nevertheless, histological features of the visceral pleura and the lungs are closely related to macroscopic characteristics of the pleura. Detailed study of this relationship and the search of morphological similarity of lesions in parietal pleura, visceral pleura, and the lung in patients with empyema could improve the diagnostic value of thoracoscopy, contribute to a rapid histological diagnosis and improve therapeutic approach to empyema. Current approach to the basic mechanisms and risk factors of remodeling of the extracellular matrix in pleural fibrosis was reviewed in the article. Analysis of this process could determine new mechanisms of extracellular matrix remodeling and ways to avoid fibrosis development in the adjacent lung tissue that, in turn, could underlie staging the empyema.
Novel inhalation devices for treatment of chronic obstructive pulmonary disease
Authors: Arkhipov V. V. , Arkhipova D. E. , Lazareva N. B. 
Published: October 2016

The aim of this review was to introduce readers to technical characteristics and advantages of recently available inhalers used for treatment of chronic obstructive pulmonary disease. Such inhalation devices as Breezehaler, Ellipta, Genuair, NEXThaler, and Respimat were described in details in this article.