bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a Spring-Loaded Impact Device to Deliver Injurious Mechanical Impacts to the Articular Cartilage Surface
Authors: Alexander Peter G. , Song Yingjie , Taboas Juan M. , Chen Faye H. , Melvin Gary M. , Manner Paul A. , Tuan Rocky S.
Published: August 2012

Objective:

Traumatic impacts on the articular joint surface in vitro are known to lead to degeneration of the cartilage. The main objective of this study was to develop a spring-loaded impact device that can be used to deliver traumatic impacts of consistent magnitude and rate and to find whether impacts cause catabolic activities in articular cartilage consistent with other previously reported impact models and correlated with the development of osteoarthritic lesions. In developing the spring-loaded impactor, the operating hypothesis is that a single supraphysiologic impact to articular cartilage in vitro can affect cartilage integrity, cell viability, sulfated glycosaminoglycan and inflammatory mediator release in a dose-dependent manner.

Design:

Impacts of increasing force are delivered to adult bovine articular cartilage explants in confined compression. Impact parameters are correlated with tissue damage, cell viability, matrix and inflammatory mediator release, and gene expression 24 hours postimpact.

Results:

Nitric oxide release is first detected after 7.7 MPa impacts, whereas cell death, glycosaminoglycan release, and prostaglandin E2 release are first detected at 17 MPa. Catabolic markers increase linearly to maximal levels after ≥36 MPa impacts.

Conclusions:

A single supraphysiologic impact negatively affects cartilage integrity, cell viability, and GAG release in a dose-dependent manner. Our findings showed that 7 to 17 MPa impacts can induce cell death and catabolism without compromising the articular surface, whereas a 17 MPa impact is sufficient to induce increases in most common catabolic markers of osteoarthritic degeneration.
Effects of Dexamethasone on Mesenchymal Stromal Cell Chondrogenesis and Aggrecanase Activity
Authors: Florine Emily M. , Miller Rachel E. , Porter Ryan M. , Evans Christopher H. , Kurz Bodo , Grodzinsky Alan J.
Published: August 2012

Objective:

Dexamethasone (Dex) is a synthetic glucocorticoid that has pro-anabolic and anticatabolic effects in cartilage tissue engineering systems, though the mechanisms by which these effects are mediated are not well understood. We tested the hypothesis that the addition of Dex to chondrogenic medium would affect matrix production and aggrecanase activity of human and bovine bone marrow stromal cells (BMSCs) cultured in self-assembling peptide and agarose hydrogels.

Design:

We cultured young bovine and adult human BMSCs in (RADA)4 self-assembling peptide and agarose hydrogels in medium containing TGF-β1±Dex and analyzed extracellular matrix composition, aggrecan cleavage products, and the effects of the glucocorticoid receptor antagonist RU-486 on proteoglycan content, synthesis, and catabolic processing.

Results:

Dex improved proteoglycan synthesis and retention in agarose hydrogels seeded with young bovine cells but decreased proteoglycan accumulation in peptide scaffolds. These effects were mediated by the glucocorticoid receptor. Adult human BMSCs showed minimal matrix accumulation in agarose, but accumulated ~50% as much proteoglycan and collagen as young bovine BMSCs in peptide hydrogels. Dex reduced aggrecanase activity in (RADA)4 and agarose hydrogels, as measured by anti-NITEGE Western blotting, for both bovine and human BMSC-seeded gels.

Conclusions:

The effects of Dex on matrix production are dependent on cell source and hydrogel identity. This is the first report of Dex reducing aggrecanase activity in a tissue engineering culture system.
IL-7 induces expression and activation of integrin α4β7 promoting naive T-cell homing to the intestinal mucosa
Authors: Cimbro Raffaello , Vassena Lia , Arthos James , Cicala Claudia , Kehrl John H. , Park Chung , Sereti Irini , Lederman Michael M. , Fauci Anthony S. , Lusso Paolo
Published: August 2012

Interleukin-7 (IL-7) is a nonredundant cytokine that plays a critical role in T-cell homeostasis and promotes immunologic reconstitution in lymphopenic hosts. Here, we show that IL-7, at doses that reflect suprahomeostatic concentrations achieved in lymphopenic hosts, is a potent and selective inducer of the gut-homing integrin α4β7 in human T cells, as documented both ex vivo and in vivo in patients enrolled in a clinical trial of IL-7 treatment. Induction of α4β7 by IL-7 occurs primarily in naive T cells and is associated with functional activation of the integrin, as indicated by increased binding activity for the specific α4β7 ligand, MAdCAM-1. The physiologic relevance of these findings was validated by the preferential homing of IL-7–treated naive human T cells to the intestinal compartment in humanized NOD/SCID/IL-2 receptor-γnull (NSG) mice. We also show that IL-7 triggers a peculiar activation program in naive T cells, characterized by the acquisition of memory-like phenotypic features and proliferation uncoupled from expression of classic T-cell activation markers. These findings provide a mechanism for the transient in vivo depletion of circulating T cells after IL-7 administration and suggest that intestinal homing and memory-like conversion of naive T cells are critical steps in the IL-7–driven immunologic reconstitution of lymphopenic hosts.
Cognitive function at 2443 μmol/l creatinine
Authors: Schneider Sabrina , Malecki Anne-Kathrin , Boenisch Olaf , Schönfeld Robby , Kielstein Jan T
Published: August 2012

Background

One hallmark of uremia is the impairment of neuro-cognitive function. Anecdotal clinical description from the early days of chronic dialysis therapy impressively illustrates the improvement of those functions by chronic hemodialysis treatment. Fortunately, today, uremia is only rarely observed in industrialized countries as many patients seek medical/nephrological attention prior to the occurrence of deadly complications of uremia.

Case presentation

We report a rare case of severe uremia and describe the day to day improvement in neuro-cognitive function by dialysis using state of the arte test battery – starting at a serum creatinine of 2443 μmol/l.

Conclusions

Especially executive functions, which are assumed to be localized in the frontal cerebral regions, are impaired in severe uremia and improve remarkably with the correction of severe uremia, i.e. initiation of dialysis.
Quality of discharge summaries prepared by first year internal medicine residents
Authors: Legault Kimberly , Ostro Jacqueline , Khalid Zahira , Wasi Parveen , You John J
Published: August 2012

Background

Patients are particularly susceptible to medical error during transitions from inpatient to outpatient care. We evaluated discharge summaries produced by incoming postgraduate year 1 (PGY-1) internal medicine residents for their completeness, accuracy, and relevance to family physicians.

Methods

Consecutive discharge summaries prepared by PGY-1 residents for patients discharged from internal medicine wards were retrospectively evaluated by two independent reviewers for presence and accuracy of essential domains described by the Joint Commission for Hospital Accreditation. Family physicians rated the relevance of a separate sample of discharge summaries on domains that family physicians deemed important in previous studies.

Results

Ninety discharge summaries were assessed for completeness and accuracy. Most items were completely reported with a given item missing in 5% of summaries or fewer, with the exception of the reason for medication changes, which was missing in 15.9% of summaries. Discharge medication lists, medication changes, and the reason for medication changes—when present—were inaccurate in 35.7%, 29.5%, and 37.7% of summaries, respectively. Twenty-one family physicians reviewed 68 discharge summaries. Communication of follow-up plans for further investigations was the most frequently identified area for improvement with 27.7% of summaries rated as insufficient.

Conclusions

This study found that medication details were frequently omitted or inaccurate, and that family physicians identified lack of clarity about follow-up plans regarding further investigations and visits to other consultants as the areas requiring the most improvement. Our findings will aid in the development of educational interventions for residents.
Far infra-red therapy promotes ischemia-induced angiogenesis in diabetic mice and restores high glucose-suppressed endothelial progenitor cell functions
Authors: Huang Po-Hsun , Chen Jaw-Wen , Lin Chih-Pei , Chen Ying-Hwa , Wang Chao-Hung , Leu Hsin-Bang , Lin Shing-Jong
Published: August 2012

Background

Far infra-red (IFR) therapy was shown to exert beneficial effects in cardiovascular system, but effects of IFR on endothelial progenitor cell (EPC) and EPC-related vasculogenesis remain unclear. We hypothesized that IFR radiation can restore blood flow recovery in ischemic hindlimb in diabetic mice by enhancement of EPCs functions and homing process.

Materials and methods

Starting at 4 weeks after the onset of diabetes, unilateral hindlimb ischemia was induced in streptozotocine (STZ)-induced diabetic mice, which were divided into control and IFR therapy groups (n = 6 per group). The latter mice were placed in an IFR dry sauna at 34°C for 30 min once per day for 5 weeks.

Results

Doppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio in the thermal therapy group was significantly increased beyond that in controls, and significantly greater capillary density was seen in the IFR therapy group. Flow cytometry analysis showed impaired EPCs (Sca-1+/Flk-1+) mobilization after ischemia surgery in diabetic mice with or without IFR therapy (n = 6 per group). However, as compared to those in the control group, bone marrow-derived EPCs differentiated into endothelial cells defined as GFP+/CD31+ double-positive cells were significantly increased in ischemic tissue around the vessels in diabetic mice that received IFR radiation. In in-vitro studies, cultured EPCs treated with IFR radiation markedly augmented high glucose-impaired EPC functions, inhibited high glucose-induced EPC senescence and reduced H2O2 production. Nude mice received human EPCs treated with IFR in high glucose medium showed a significant improvement in blood flow recovery in ischemic limb compared to those without IFR therapy. IFR therapy promoted blood flow recovery and new vessel formation in STZ-induced diabetic mice.

Conclusions

Administration of IFR therapy promoted collateral flow recovery and new vessel formation in STZ-induced diabetic mice, and these beneficial effects may derive from enhancement of EPC functions and homing process.
The LCMV gp33-specific memory T cell repertoire narrows with age
Authors: Bunztman Adam , Vincent Benjamin G , Krovi Harsha , Steele Shaun , Frelinger Jeffrey A
Published: August 2012

Background

The memory response to LCMV in mice persists for months to years with only a small decrease in the number of epitope specific CD8 T cells. This long persistence is associated with resistance to lethal LCMV disease. In contrast to studies focused on the number and surface phenotype of the memory cells, relatively little attention has been paid to the diversity of TCR usage in these cells. CD8+T cell responses with only a few clones of identical specificity are believed to be relatively ineffective, presumably due to the relative ease of virus escape. Thus, a broad polyclonal response is associated with an effective anti-viral CD8+T cell response.

Results

In this paper we show that the primary CD8+T cell response to the LCMV gp33-41 epitope is extremely diverse. Over time while the response remains robust in terms of the number of gp33-tetramer+T cells, the diversity of the response becomes less so. Strikingly, by 26 months after infection the response is dominated by a small number TCRβ sequences. In addition, it is of note the gp33 specific CD8+T cells sorted by high and low tetramer binding populations 15 and 22 months after infection. High and low tetramer binding cells had equivalent diversity and were dominated by a small number of clones regardless of the time tested. A similar restricted distribution was seen in NP396 specific CD8+T cells 26 months after infection. The identical TCRVβ sequences were found in both the tetramerhiand tetramerlobinding populations. Finally, we saw no evidence of public clones in the gp33-specific response. No CDR3 sequences were found in more than one mouse.

Conclusions

These data show that following LCMV infection the CD8+gp33-specific CD8 T cell response becomes highly restricted with enormous narrowing of the diversity. This narrowing of the repertoire could contribute to the progressively ineffective immune response seen in aging.
Imbalance of placental regulatory T cell and Th17 cell population dynamics in the FIV-infected pregnant cat
Authors: Boudreaux Crystal E , Chumbley Lyndon B , Scott Veronica L , Wise Dwayne A , Coats Karen S
Published: August 2012

Background

An appropriate balance in placental regulatory T cells (Tregs), an immunosuppressive cell population, and Th17 cells, a pro-inflammatory cell population, is essential in allowing tolerance of the semi-allogeneic fetus. TGF-β and IL-6 are cytokines that promote differentiation of Tregs and Th17 cells from a common progenitor; aberrant expression of the cytokines may perturb the balance in the two cell populations. We previously reported a pro-inflammatory placental environment with decreased levels of FoxP3, a Treg marker, and increased levels of IL-6 in the placentas of FIV-infected cats at early pregnancy. Thus, we hypothesized that FIV infection in the pregnant cat causes altered placental Treg and Th17 cell populations, possibly resulting in placental inflammation.

Methods

We examined the effect of FIV infection on Treg and Th17 populations in placentas at early pregnancy using quantitative confocal microscopy to measure FoxP3 or RORγ, a Th17 marker, and qPCR to quantify expression of the key cytokines TGF-β and IL-6.

Results

FoxP3 and RORγ were positively correlated in FIV-infected placentas at early pregnancy, but not placentas from normal cats, indicating virus-induced alteration in the balance of these cell populations. In control cats the expression of IL-6 and RORγ was positively correlated as predicted, but this relationship was disrupted in infected animals. TGF-β was reduced in infected queens, an occurrence that could dysregulate both Treg and Th17 cell populations. Co-expression analyses revealed a highly significant positive correlation between IL-6 and TGF-β expression in control animals that did not occur in infected animals.

Conclusion

Collectively, these data point toward potential disruption in the balance of Treg and Th17 cell populations that may contribute to FIV-induced inflammation in the feline placenta.
Neuroendocrine tumor in gastric adenoma: a diagnostic pitfall mimicking invasive adenocarcinoma
Authors: Lee Sun-Mi , Ahn Soomin , Lee Yun Kyung , Jang Kee-Taek , Park Cheol Keun , Kim Kyoung-Mee
Published: August 2012

Neuroendocrine tumor (NET) in adenoma of the gastrointestinal tract is a rare mixed glandular-endocrine neoplasm and has uncommonly been described mostly in the colon. Histologically, this tumor is composed of a predominant proportion of benign adenomatous component and a small portion of well-differentiated NE component. Only three cases of NET in gastric adenoma have been reported in the literature. We present 4 cases of NET in gastric adenoma mimicking invasive adenocarcinoma. The NETs were 0.62 mm to 4.1 mm in size and located at the basal lamina propria, muscularis mucosa and submucosa. Histologically, NETs consisted of nests, cords, tubules, and clusters of cells that predominantly interposed between the foveolar base without disturbing the overall polyp architecture. The lesions were completely removed by endoscopic submucosal dissection in three cases and in one case, subtotal gastrectomy was performed because endoscopic biopsy was invasive adenocarcinoma. The patients’ clinical course was uneventful without an evidence of recurrence or metastasis. The recognition of NET in gastric adenoma will help avoid potential diagnostic pitfalls masquerading as invasvie adenocarcinomas posed by their infiltrative pattern into submucosa.

Virtual slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1688552293761001
Implication of protein kinase R Gene quantification in hepatitis C Virus Genotype 4 induced Hepatocarcinogenesis
Authors: Mohamed Amal A , Nada Ola H , El Desouky Mohamed A
Published: August 2012

Background

Protein kinase RNA (PKR-regulated) is a double-stranded RNA activated protein kinase whose expression is induced by interferon. The role of PKR in cell growth regulation is controversial, with some studies supporting a tumour suppressor function and others suggesting a growth-promoting role. However, it is possible that the function of PKR varies with the type of cancer in question.

Methods

We report here a detailed study to evaluate the function of PKR in hepatitis C virus genotype 4 (HCV-4) infected patients. PKR gene was quantitated in HCV related malignant and non-malignant liver tissue by RT-PCR technique and the association of HCV core and PKR was assessed.

Results

If PKR functions as a tumour suppressor in this system, its expression would be higher in chronic hepatitis tissues. On the contrary our study demonstrated the specific association of HCV-4 with PKR expressed in hepatocellular carcinoma (HCC) tissues, leading to an increased gene expression of the kinase in comparison to chronic hepatitis tissues. This calls into question its role as a tumour suppressor and suggests a positive regulatory role of PKR in growth control of liver cancer cells. One limitation of most of other studies is that they measure the levels rather than the quantitation of PKR gene.

Conclusion

The findings suggest that PKR exerts a positive role in cell growth control of HCV-4 related HCC, obtaining a cut-off value for PKR expression in liver tissue provides the first evidence for existence of a viral activator of PKR.

Virtual Slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1267826959682402.
Analysis of naltrexone and its metabolite 6-beta-naltrexol in serum with high-performance liquid chromatography
Authors: Heinälä Pekka , Lahti Tuuli , Sinclair David , Ariniemi Kari , Lillsunde Pirjo , Alho Hannu
Published: August 2012

Background

Naltrexone has been proven to be an effective treatment option for the treatment of alcohol dependency. In this article we introduce a reliable and simple method developed for the simultaneous determination of naltrexone and 6-β-naltrexol in human serum by using high-performance liquid chromatography (HPLC).

Findings

Liquid-liquid extraction with butyl acetate from basic solutions (pH 9) was chosen for extraction with nalorphine as an internal standard (IS). Analytes were back-extracted from organic solvent into perchloric acid. The acid extract was chromatographed by HPLC with a reverse-phase ODS-column and electrochemical detector. The mobile phase was a NaH2PO4-solution with acetonitrile as an organic modifier and octanesulphonic acid and tetraethylammonium hydrogen sulphate as ion-pair reagents. The recovery of the extraction method was 48% for naltrexone and 75% for 6-β-naltrexol. The limit of quantification was 5.0 ng/ml for naltrexone and 1.0 ng/ml for 6-β-naltrexol. The analysed concentrations of naltrexone differed from the theoretic concentrations by 0.7 to 2.3% and those of 6-β-naltrexol by 2.6%. The relative standard deviation of within-day assay was from 0.9 to 5.7% for naltrexone and from 0.8 to 4.2% for 6-β-naltrexol; for the between-day assay it was 5.7% and 4.2%, respectively.

Conclusions

Our results indicate that the developed method is suitable for determination of naltrexone and 6-β-naltrexol in human serum.
Contribution of uric acid to cancer risk, recurrence, and mortality
Authors: Fini Mehdi A , Elias Anthony , Johnson Richard J , Wright Richard M
Published: August 2012

Two risk factors for the development and progression of cancers that are amenable to life style modification are chronic inflammation and the metabolic syndrome. This review proposes two new targets that may mechanistically integrate inflammation and metabolic syndrome, have been largely ignored, and are known to be druggable. Recent evidence has demonstrated that elevated serum uric acid (hyperuricemia) is associated with excess cancer risk, recurrence, and mortality. Although uric acid (UA) can function as a systemic antioxidant, its pro‐inflammatory properties have been postulated to play an important role in the pathogenesis of cancer. Furthermore, obesity, Type 2 Diabetes Mellitus (T2DM), and the metabolic syndrome (MetS) are also associated with excess cancer, chronic inflammation, and with hyperuricemia, suggesting that UA may represent an important link between these disorders and the development of cancer. While pharmacological modulation of hyperuricemia could in principal augment anti‐cancer therapeutic strategies, some cancer cells express low intracellular levels of the enzyme Xanthine Oxidoreductase (XOR) that are associated with increased cancer aggressiveness and poor clinical outcome. Thus, systemic pharmacological inhibition of XOR may worsen clinical outcome, and specific strategies that target serum uric acid (SUA) without inhibiting tumor cell XOR may create new therapeutic opportunities for cancer associated with hyperuricemia. This review will summarize the evidence that elevated SUA may be a true risk factor for cancer incidence and mortality, and mechanisms by which UA may contribute to cancer pathogenesis will be discussed in the hope that these will identify new opportunities for cancer management.
Activity of the neuroendocrine axes in patients with polymyalgia rheumatica before and after TNF-α blocking etanercept treatment
Authors: Kreiner Frederik Flindt , Galbo Henrik
Published: August 2012

Introduction

In this study, we evaluated the activity of the neuroendocrine axes in patients with polymyalgia rheumatica (PMR) before and after tumor necrosis factor (TNF)-α-blocking etanercept treatment, which previously has been shown to reduce interleukin 6 (IL-6) and C-reactive protein (CRP) markedly in PMR.

Methods

Plasma samples were collected from 10 glucocorticoid-naïve patients with PMR and 10 matched controls before and after etanercept treatment (25 mg biweekly for 2 weeks). The primary end points were pre- and posttreatment levels of adrenocorticotropic hormone (ACTH), cortisol, adrenaline, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), prolactin, and insulin-like growth factor 1 (IGF-1).

Results

Before TNF-α-blocking treatment, plasma TNF-α, ACTH, and cortisol levels were higher in patients versus controls (P < 0.05 and P < 0.001, respectively); during TNF-α blockade in patients, levels of both hormones decreased (P < 0.05 and P < 0.01, respectively), whereas levels in controls increased (P < 0.05), abolishing the pretreatment differences. Pretreatment adrenaline levels were more than twice as high in patients than in controls (P < 0.01); after treatment in patients, levels had decreased (P < 0.05) but remained higher versus controls (P < 0.05). Levels of the other hormones never differed significantly between groups (P > 0.05).

Conclusions

In PMR, TNF-α may increase the activities of the hypothalamic-pituitary-adrenal and the hypothalamic-sympthoadrenomedullary axes. Secretion of TSH, FSH, prolactin, and IGF-1 is not clearly changed in PMR.

Trial registration

ClinicalTrials.gov (NCT00524381).
Staphylococcus aureus Panton-Valentine leukocidin induces an inflammatory response in human phagocytes via the NLRP3 inflammasome
Authors: Holzinger Dirk , Gieldon Laura , Mysore Vijayashree , Nippe Nadine , Taxman Debra J , Duncan Joseph A , Broglie Peter M , Marketon Kristina , Austermann Judith , Vogl Thomas , Foell Dirk , Niemann Silke , Peters Georg , Roth Johannes , Löffler Bettina
Published: August 2012

Activation of the NLRP3-inflammasome contributes to Staphylococcus aureus PVL-associated diseases, such as necrotizing pneumonia.

The Staphylococcus aureus pore-forming toxin PVL is most likely causative for life-threatening necrotizing infections, which are characterized by massive tissue inflammation and necrosis. Whereas the cytotoxic action of PVL on human neutrophils is already well established, the PVL effects on other sensitive cell types, such as monocytes and macrophages, are less clear. In this study, we used different types of human leukocytes (neutrophils, monocytes, macrophages, lymphocytes) to investigate cell-specific binding of PVL subunits and subsequent proinflammatory and cytotoxic effects. In all PVL-sensitive cells, we identified the binding of the subunit LukS-PV as the critical factor for PVL-induced cytotoxicity, which was followed by binding of LukF-PV. LukS-PV binds to monocytes, macrophages, and neutrophils but not to lymphocytes. Additionally, we showed that PVL binding to monocytes and macrophages leads to release of caspase-1-dependent proinflammatory cytokines IL-1β and IL-18. PVL activates the NLRP3 inflammasome, a signaling complex of myeloid cells that is involved in caspase-1-dependent IL-1β processing in response to pathogens and endogenous danger signals. Specific inhibition of this pathway at several steps significantly reduced inflammasome activation and subsequent pyronecrosis. Furthermore, we found that PAMPs and DAMPs derived from dying neutrophils can dramatically enhance this response by up-regulating pro-IL-1β in monocytes/macrophages. This study analyzes a specific host signaling pathway that mediates PVL-induced inflammation and cytotoxicity, which has high relevance for CA-MRSA-associated and PVL-mediated pathogenic processes, such as necrotizing infections.
Recurrence patterns of bladder transitional cell carcinoma after radical cystectomy
Authors: Kim Bohyun , Choi Hyuck Jae , Kim Mi-hyun , Cho Kyung-Sik
Published: August 2012

Background

Multidetector computed tomography (MDCT) is widely accepted as an effective imaging modality in monitoring for bladder cancer recurrence after radical cystectomy. Elucidating the pattern of bladder cancer recurrence on CT can increase the diagnostic accuracy.

Purpose

To evaluate the recurrence patterns of transitional cell carcinoma of the bladder and the factors associated with cancer recurrence.

Material and Methods

One hundred and forty-nine consecutive patients (mean age, 66.55 years; range, 32–86 years) who underwent preoperative contrast-enhanced CT and radical cystectomy were included in this study. The presence, site, and time of tumor recurrence were recorded retrospectively by two radiologists in a consensus fashion. The association of tumor recurrence and tumor factors (T stage, lymph node metastasis, nuclear grade, and tumor diameter) were also evaluated using multiple logistic regression analysis and Kaplan-Meier statistics.

Results

Tumor recurrence occurred in 60 patients (40.3%) with a mean time of 14 months (range, 1–64 months). The sites of recurrence included the operation site ( n = 20), lymph node ( n = 20), bone ( n = 11), liver ( n = 6), lung ( n = 5), upper urinary tract ( n = 4), colon ( n = 3), adrenal gland ( n = 2), peritoneum ( n = 1), abdominal wall ( n = 1), psoas muscle ( n = 1), and penile skin ( n = 1). Tumor recurrence was found to be associated with advanced T stage ( P = 0.002) and lymph node metastasis ( P < 0.001).

Conclusion

Transitional cell carcinomas of the bladder recur more frequently at the operation site and lymph node, and T-stage and lymph node metastasis are closely associated with tumor recurrence.
Scenario Trees and Policy Selection for Multistage Stochastic Programming Using Machine Learning
Authors: Defourny Boris , Ernst Damien , Wehenkel Louis
Published: August 2012

In the context of multistage stochastic optimization problems, we propose a hybrid strategy for generalizing to nonlinear decision rules, using machine learning, a finite data set of constrained vector-valued recourse decisions optimized using scenario-tree techniques from multistage stochastic programming. The decision rules are based on a statistical model inferred from a given scenario-tree solution and are selected by out-of-sample simulation given the true problem. Because the learned rules depend on the given scenario tree, we repeat the procedure for a large number of randomly generated scenario trees and then select the best solution (policy) found for the true problem. The scheme leads to an ex post selection of the scenario tree itself. Numerical tests evaluate the dependence of the approach on the machine learning aspects and show cases where one can obtain near-optimal solutions, starting with a “weak” scenario-tree generator that randomizes the branching structure of the trees.
Base Model Combination Algorithm for Resolving Tied Predictions forK-Nearest Neighbor OVA Ensemble Models
Authors: Lutu Patricia E. N. , Engelbrecht Andries P.
Published: August 2012

Model aggregation is the process of constructing several base models that are then combined into a single model for prediction. Ensemble classification has been studied by many researchers and found to provide significant performance improvements over single models. This paper presents a new base model combination algorithm for K-nearest neighbor (KNN) ensemble models based on One-Versus-All (OVA) classification. The proposed algorithm uses two decision functions to determine the best prediction among the many predictions provided by the base models. It is demonstrated in this paper that tied or conflicting predictions can be effectively resolved when a probabilistic function and a distance function are used by a combination algorithm for OVA KNN base model predictions. The resolution of tied predictions leads to improvements in predictive performance.
Psychophysical and Neural Evidence for Emotion-Enhanced Perceptual Vividness
Authors: Todd Rebecca M. , Talmi Deborah , Schmitz Taylor W. , Susskind Josh , Anderson Adam K.
Published: August 2012

Highly emotional events are associated with vivid “flashbulb” memories. Here we examine whether the flashbulb metaphor characterizes a previously unknown emotion-enhanced vividness (EEV) during initial perceptual experience. Using a magnitude estimation procedure, human observers estimated the relative magnitude of visual noise overlaid on scenes. After controlling for computational metrics of objective visual salience, emotional salience was associated with decreased noise, or heightened perceptual vividness, demonstrating EEV, which predicted later memory vividness. Event-related potentials revealed a posterior P2 component at ∼200 ms that was associated with both increased emotional salience and decreased objective noise levels, consistent with EEV. Blood oxygenation level-dependent response in the lateral occipital complex (LOC), insula, and amygdala predicted online EEV. The LOC and insula represented complimentary influences on EEV, with the amygdala statistically mediating both. These findings indicate that the metaphorical vivid light surrounding emotional memories is embodied directly in perceptual cortices during initial experience, supported by cortico-limbic interactions.
Effective Connectivity of the Human Cerebellum during Visual Attention
Authors: Kellermann Thilo , Regenbogen Christina , De Vos Maarten , Mößnang Carolin , Finkelmeyer Andreas , Habel Ute
Published: August 2012

Insights from both lesion and neuroimaging studies increasingly substantiate the view that the human cerebellum not only serves motor control but also supports various cognitive processes. Higher cognitive functions like working memory or executive control have been associated with the phylogenetically younger parts of the cerebellum, crus I and crus II. Functional connectivity studies corroborate this notion as activation of the cerebellum correlates with activity in numerous areas of the cerebral cortex. Moreover, these cerebrocerebellar loops were shown to be topographically organized. We used an attention-to-motion paradigm to elaborate on the effective connectivity of cerebellar crus I during visual attention. Psychophysiological interaction analyses demonstrated enhanced connectivity of the cerebellum—during attention—with dorsal visual stream regions including posterior parietal cortex (PPC) and left secondary visual cortex (V5). Dynamic causal modeling revealed a modulation of the connections from V5 to PPC and from crus I to V5 by attention. Remarkably, the influence which V5 exerted on PPC was reduced during attention, resulting in a suppression of the sensitivity of PPC to bottom-up information. Moreover, the sensitivity of V5 populations to inputs from crus I was increased under attention. This might underscore the presumed role of the cerebellum as a state estimator that provides hierarchically lower regions (V5) with top-down predictions, which in turn might be based on endogenous inputs from PPC to the cerebellum. These results are in line with formulations of attention in predictive coding, where attention increases the precision or sensitivity of hierarchically lower neuronal populations that may encode prediction error.
Alzheimer's β-Secretase (BACE1) Regulates the cAMP/PKA/CREB Pathway Independently of β-Amyloid
Authors: Chen Yaomin , Huang Xiumei , Zhang Yun-wu , Rockenstein Edward , Bu Guojun , Golde Todd E. , Masliah Eliezer , Xu Huaxi
Published: August 2012

β-Amyloid protein (Aβ), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from proteolytic cleavages of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. BACE1 is the rate-limiting enzyme for Aβ production, and an increase in BACE1 level/activity contributes to the pathogenesis of sporadic AD. In addition to cleaving APP for Aβ generation, BACE1 plays multiple physiological roles including the regulation of synaptic functions. Here, we found that overexpression of BACE1 reduces cAMP response element binding protein (CREB) phosphorylation, protein kinase A (PKA) activity, and cAMP levels, whereas downregulation of BACE1 has the opposite effect. We showed that BACE1's effect is independent of its activity for Aβ production, which is corroborated by the observation that BACE1 transgenic mice have impaired learning/memory in the absence of neurotoxic human Aβ. Furthermore, we demonstrated that BACE1 interacts via its transmembrane domain with adenylate cyclase, resulting in reduction of cellular cAMP levels and thus PKA inactivation and reduced CREB phosphorylation. Our study suggests that in addition to its function as the β-secretase to produce Aβ, BACE1 may contribute to the memory and cognitive deficits typical of AD by regulating the cAMP/PKA/CREB pathway, which is important for memory functions.
Amygdalar Stimulation Produces Alterations on Firing Properties of Hippocampal Place Cells
Authors: Kim Eun Joo , Kim Earnest S. , Park Mijeong , Cho Jeiwon , Kim Jeansok J.
Published: August 2012

Stress is a biologically ubiquitous factor that, when perceived uncontrollable by humans and animals, can have lingering adverse effects on brain and cognitive functions. We have previously reported that rats that experienced inescapable-unpredictable stress subsequently exhibited decreased stability of firing rates of place cells in the CA1 hippocampus, accompanied by impairments in CA1 long-term synaptic potentiation and spatial memory consolidation. Because the elevated level of glucocorticoid hormones and the heightened amygdalar activity have been implicated in the emergence of stress effects on the hippocampus, we investigated whether administration of corticosterone and electrical stimulation of the amygdala can produce stress-like alterations on hippocampal place cells. To do so, male Long–Evans rats chronically implanted with tetrodes in the hippocampus and stimulating electrodes in the amygdala were placed on a novel arena to forage for randomly dispersed food pellets while CA1 place cells were monitored across two recording sessions. Between sessions, animals received either corticosterone injection or amygdalar stimulation. We found that amygdalar stimulation reliably evoked distress behaviors and subsequently reduced the pixel-by-pixel correlation of place maps across sessions, while corticosterone administration did not. Also, the firing rates of place cells between preamygdalar and postamygdalar stimulation recording sessions were pronouncedly different, whereas those between precorticosterone and postcorticosterone injection recording sessions were not. These results suggest that the heightened amygdalar activity, but not the elevated level of corticosterone per se, reduces the stability of spatial representation in the hippocampus by altering the firing rates of place cells in a manner similar to behavioral stress.
Multiple Roles for Mammalian Target of Rapamycin Signaling in Both Glutamatergic and GABAergic Synaptic Transmission
Authors: Weston Matthew C. , Chen Hongmei , Swann John W.
Published: August 2012

The mammalian target of rapamycin (mTOR) signaling pathway in neurons integrates a variety of extracellular signals to produce appropriate translational responses. mTOR signaling is hyperactive in neurological syndromes in both humans and mouse models that are characterized by epilepsy, autism, and cognitive disturbances. In addition, rapamycin, a clinically important immunosuppressant, is a specific and potent inhibitor of mTOR signaling. While mTOR is known to regulate growth and synaptic plasticity of glutamatergic neurons, its effects on basic parameters of synaptic transmission are less well studied, and its role in regulating GABAergic transmission is unexplored. We therefore performed an electrophysiological and morphological comparison of glutamatergic and GABAergic neurons in which mTOR signaling was either increased by loss of the repressor Pten or decreased by treatment with rapamycin. We found that hyperactive mTOR signaling increased evoked synaptic responses in both glutamatergic and GABAergic neurons by ∼50%, due to an increase in the number of synaptic vesicles available for release, the number of synapses formed, and the miniature event size. Prolonged (72 h) rapamycin treatment prevented these abnormalities and also decreased synaptic transmission in wild-type glutamatergic, but not GABAergic, neurons. Further analyses suggested that hyperactivation of the mTOR pathway also impairs presynaptic function, possibly by interfering with vesicle fusion. Despite this presynaptic impairment, the net effect of Pten loss is enhanced synaptic transmission in both GABAergic and glutamatergic neurons, which has numerous implications, depending on where in the brain mutations of an mTOR suppressor gene occur.
Gβ3Is Required for Normal Light ON Responses and Synaptic Maintenance
Authors: Dhingra Anuradha , Ramakrishnan Hariharasubramanian , Neinstein Adam , Fina Marie E. , Xu Ying , Li Jian , Chung Daniel C. , Lyubarsky Arkady , Vardi Noga
Published: August 2012

Heterotrimeric G-proteins, comprising Gα and Gβγ subunits, couple metabotropic receptors to various downstream effectors and contribute to assembling and trafficking receptor-based signaling complexes. A G-protein β subunit, Gβ3, plays a critical role in several physiological processes, as a polymorphism in its gene is associated with a risk factor for several disorders. Retinal ON bipolar cells express Gβ3, and they provide an excellent system to study its role. In the ON bipolar cells, mGluR6 inverts the photoreceptor's signal via a cascade in which glutamate released from photoreceptors closes the TRPM1 channel. This cascade is essential for vision since deficiencies in its proteins lead to complete congenital stationary night blindness. Here we report that Gβ3participates in the G-protein heterotrimer that couples mGluR6 to TRPM1. Gβ3deletion in mouse greatly reduces the light response under both scotopic and photopic conditions, but it does not eliminate it. In addition, Gβ3deletion causes mislocalization and downregulation of most cascade elements and modulators. Furthermore, Gβ3may play a role in synaptic maintenance since in its absence, the number of invaginating rod bipolar dendrites is greatly reduced, a deficit that was not observed at 3 weeks, the end of the developmental period.
In VivoReversible Regulation of Dendritic Patterning by Afferent Input in Bipolar Auditory Neurons
Authors: Wang Yuan , Rubel Edwin W
Published: August 2012

Afferent input regulates neuronal dendritic patterning locally and globally through distinct mechanisms. To begin to understand these mechanisms, we differentially manipulate afferent inputin vivoand assess effects on dendritic patterning of individual neurons in chicken nucleus laminaris (NL). Dendrites of NL neurons segregate into dorsal and ventral domains, receiving excitatory input from the ipsilateral and contralateral ears, respectively, via nucleus magnocellularis (NM). Blocking action potentials from one ear, by either cochlea removal or temporary treatment with tetrodotoxin (TTX), leads to rapid and significant retraction of affected NL dendrites (dorsal ipsilaterally and ventral contralaterally) within 8 h compared with the other dendrites of the same neurons. The degree of retraction is comparable with that induced by direct deafferentation resulting from transection of NM axons. Importantly, when inner ear activity is allowed to recover from TTX treatments, retracted NL dendrites regrow to their normal length within 48 h. The retraction and growth involve elimination of terminal branches and addition of new branches, respectively. Examination of changes in NL dendrites at 96 h after unilateral cochlea removal, a manipulation that induces cell loss in NM and persistent blockage of afferent excitatory action potentials, reveals a significant correlation between cell death in the ipsilateral NM and the degree of dendritic retraction in NL. These results demonstrate that presynaptic action potentials rapidly and reversibly regulate dendritic patterning of postsynaptic neurons in a compartment specific manner, whereas long-term dendritic maintenance may be regulated in a way that is correlated with the presence of silent presynaptic appositions.
Elimination of GRK2 from Cholinergic Neurons Reduces Behavioral Sensitivity to Muscarinic Receptor Activation
Authors: Daigle Tanya L. , Caron Marc G.
Published: August 2012

Although G-protein-coupled receptor kinase 2 (GRK2) is the most widely studied member of a family of kinases that has been shown to exert powerful influences on a variety of G-protein-coupled receptors, its role in the brain remains largely unknown. Here we report the localization of GRK2 in the mouse brain and generate novel conditional knock-out (KO) mice to assess the physiological importance of this kinase in cholinergic neurons. Mice with the selective deletion of GRK2 in this cell population (ChATIRES-creGrk2f/fKO mice) exhibit reduced behavioral responsiveness to challenge with oxotremorine-M (Oxo-M), a nonselective muscarinic acetylcholine receptor agonist. Specifically, Oxo-M-induced hypothermia, hypolocomotion, and salivation were markedly reduced in these animals, while analgesic responses were unaltered. In contrast, we found that GRK2 deficiency in cholinergic neurons does not alter cocaine-induced psychomotor activation, behavioral sensitization, or conditioned place preference. These results demonstrate that the elimination of GRK2 in cholinergic neurons reduces sensitivity to select muscarinic-mediated behaviors, while dopaminergic effects remain intact and further suggests that GRK2 may selectively impair muscarinic acetylcholine receptor-mediated functionin vivo.
Neurotrophic Effects of Serum- and Glucocorticoid-Inducible Kinase on Adult Murine Mesencephalic Dopamine Neurons
Authors: Chen Xiqun , Tagliaferro Patricia , Kareva Tatyana , Yarygina Olga , Kholodilov Nikolai , Burke Robert E.
Published: August 2012

Mesencephalic dopamine neurons are central to many aspects of human cognition, motivational, and motor behavior, and they are uniquely vulnerable to degenerative neurologic disorders such as Parkinson's disease. There is growing evidence that in the mature brain these neurons not only remain responsive to neurotrophic support, but are dependent on it for viability and function. Little is known of the cellular signaling pathways that mediate this support, although some evidence suggests that protein kinase Akt/PKB may play such a role. Another candidate for such a role is serum- and glucocorticoid-inducible kinase (SGK), a member of the AGC kinase family that is closely related to Akt. We have herein examined the responsiveness of adult mouse dopamine neuronsin vivoto overexpression of wild-type and a constitutively active form of SGK by use of viral vector transfer in normal mice and both before and after 6-OHDA lesion. We find that SGK induces a broad spectrum of neurotrophic effects on these neurons, including induction of neuronal hypertrophy, protection from both neuron death and neurotoxin-induced retrograde axonal degeneration, and axon regeneration. Given the diverse and robust effects of SGK on these neurons, and its abundant expression in them, we suggest that SGK, like closely related Akt, may play a role in their responsiveness to neurotrophic factors and in adult maintenance. It therefore offers a novel target for therapeutic development.
Anwendung dynamisch erweiterter Beobachter zur robusten Fehlerisolation
Authors: Wahrburg Arne
Published: August 2012

Dieser Beitrag befasst sich mit dem Entwurf von dynamisch erweiterten Fehlerisolationsbeobachtern (FIOs). Dazu wird zunächst eine Methode zum Entwurf dynamischer Entkopplungsregler vorschlagen. Basierend auf der Dualität von Entkopplungsregelungen und Fehlerisolationsbeobachtern lässt sich hieraus ein Verfahren zum Entwurf von dynamischen Fehlerisolationsbeobachtern ableiten, welches gegenüber klassischen FIOs zusätzliche Freiheitsgrade bietet. Diese werden in diesem Beitrag dazu genutzt, die Robustheit bezüglich hochfrequenter Störungen zu verbessern.
Entwurf vernetzter ereignisbasierter Regelungssysteme mit Kommunikationsbeschränkungen
Authors: Molin Adam , Hirche Sandra
Published: August 2012

Der Betrieb komplexer, verteilter Regelungssysteme erfordert eine effiziente Nutzung vorhandener Ressourcen. Kürzlich erzielte Ergebnisse zeigen wesentliche Vorteile einer ereignisbasierten Regelung verglichen mit herkömmlichen Entwurfsmethoden mit periodischer Abtastung, wenn die Kommunikationsbandbreite, der Energieverbrauch oder die Rechenleistung beschränkt sind. Dieser Beitrag beschäftigt sich mit dem Entwurf ereignisbasierter Regelungen mehrerer heterogener Teilsysteme, deren Rückführschleifen über ein gemeinsames Kommunikationssystem verkoppelt sind. Mittels Zustandsaggregation wird eine dezentrale ereignisbasierte Regelungsstruktur entworfen und Stabilitätsbedinungen hergeleitet, unter welchen das Gesamtsystem stochastisch stabil ist. Unter diesen Stabilitätsbedingungen lässt sich zeigen, dass der vorgeschlagene Regelungsentwurf asymptotisch optimal mit zunehmender Anzahl an Teilsystemen ist.
Ansätze zur Berechnung und schnellen Auswertung expliziter modellprädiktiver Regelgesetze
Authors: Kastsian Martin , Jost Michael , Mönnigmann Martin
Published: August 2012

Die explizite modellprädiktive Regelung (EMPC) zeichnet sich dadurch aus, dass zur Betriebszeit des Reglers keine numerischen Optimierungsaufgaben gelöst werden müssen. Obwohl die EMPC nur für Systeme niedriger Ordnung mit wenigen Beschränkungen und kurzen Horizonten in Frage kommt, ist sie eine Alternative bei sehr kurzen Abtastzeiten und bei strengen Echtzeitanforderungen. Wir schlagen eine neue Methode zur Berechnung von EMPC Regelgesetzen vor und zeigen einen neuen Ansatz zur Beschleunigung der Auswertung dieser Regelgesetze mit Hilfe von massiv nebenläufigen Schaltnetzwerken auf.