bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Ultra-porous Titanium Dioxide Ceramic with Excellent Biocompatibility
Authors: Sabetrasekh Roya , Tiainen Hanna , Lyngstadaas S. Petter , Reseland Janne , Haugen Håvard
Published: January 2010

The current study compares biocompatibility, cell growth and morphology, pore diameter distribution, and interconnectivity of a novel titanium dioxide (TiO2) bone graft substitute granules with three different commercially available bone graft granules Natix®, Straumann® BoneCeramic, and Bio-Oss®. Human primary mesenchymal stem cells were cultured on the bone graft substitutes and cell viability and proliferation were evaluated after 1 and 3 days. The microstructural properties of the bone graft substitutes were evaluated by scanning electron microscopy, micro-computed tomography analysis, and mechanical testing. The cell viability and proliferation, porosity, interconnectivity, open pore size, and surface area-to-volume ratio of TiO2 granules were significantly higher than commercial bone granules (Bio-Oss® and Straumann ® BoneCeramic).
Network Hopes
Authors: Tapia Andrea H. , Ortiz Julio Angel
Published: January 2010

In this work, the authors examine four cases of municipalities that have attempted to create municipal-sponsored wireless broadband networks. In each of these cases, one of the reasons given for establishing the network was to engage the citizens in their community and government. In each of these cases, the efforts have failed in some way. This problem rests on several assumptions. First, these municipalities believe in the importance and need to increase civic engagement, public participation in local government. They also believe that one way to do this is through increasing access to broadband Internet. In this article, we argue against a simplistic, deterministic, utopian view of information and communication technologies. We argue that in the case of local governments, choices made by government officials to solve social problems with technology are often made out of hope, frustration, inadequate funding, and inadequate knowledge. These public technology projects are often met with failure and often lead to further distance and mistrust between local governments, public officials, and citizens.
Climate change, flooding and the media in Britain
Authors: Gavin Neil T. , Leonard-Milsom Liam , Montgomery Jessica
Published: January 2010

The weather is a preoccupation of the British public, and flooding has become a salient feature of their experience. Climate science also has important things to say about the prevalence, distribution and dangers of rainfall and flooding, and what we should expect from global warming. This paper looks at British press coverage of flooding, and at the connections made between this theme and climate change. It aims to expose longitudinal patterning, and assess how common the connection is. From here the analysis moves to specific cases of high profile flooding events for a detailed exploration of the tone and tenor, and discursive contours of reports. The results suggest the media’s contribution to genuine debate is mixed, that the connection between common forms of reportage and our scientific understanding of the phenomena is often tenuous. The paper explores the implications for the way the politics of climate change plays out.
Christian lay understandings of preimplantation genetic diagnosis
Authors: Doolin Bill , Motion Judy
Published: January 2010

Focus groups were used to analyse Christian lay public understanding of preimplantation genetic diagnosis (PGD), a relatively new biomedical practice. The paper explores how this often controversial genetic technology was contextualised and interpreted through the intersection of religious values and beliefs, secular and cultural knowledges, and lived experience and emotion. For the lay people in our study, PGD often created moral dilemmas that could not necessarily be resolved through Christian beliefs and teaching, but which required the expression of empathy and compassion. The findings emphasise the heterogeneity in individuals’ interpretations of scientific issues and reinforce the need to consider public understanding of science and technology in terms of public concerns and meaning.
Collapsing the Global and the Local through Interscalar Strategies: a Glurbanization Perspective
Authors: Matusitz Jonathan
Published: January 2010

This article examines glurbanization, a model stating that urban transformation through interscalar strategies can increase the ability and status of global city-regions to develop global competitive advantages. Interscalar strategies refer to the use of scaling processes through strategic cross-border restructuration and multiple localities. Localities are groups or communities such as neighborhoods, municipalities, suburbs, regions, and urban zones. Interscaling implies a network or relationship between each of these localities, each being at a different scale. Glurbanization, then, collapses the global and the local. It does not follow a hierarchical design whereby the nation-state controls how things work; rather, globalization now happens from both ‘below’ and ‘above’.
On the History and Potentials of Evolutionary Metaphors in Urban Planning
Authors: Mehmood Abid
Published: January 2010

This article looks at the history of evolutionary thought in urban planning. It classifies the use of evolutionary metaphors in three broad theoretical streams. The first stream of thought considers the existence of vital forces and energy flows (vitalism) in an urban form. The second stream provides a holistic-organic (organicism) perspective to the city. The third stream, contemporarily very popular in social sciences, is based on the natural evolutionary theories of Lamarck and Darwin to look at urban dynamics. It is suggested that the flexible-adaptive and self-regulatory nature of evolutionary metaphors can support a holistic-integrative perspective to urban and regional planning.
Stories as Instruments
Authors: Loyer Erik
Published: January 2010

In this article, the author describes a design method for independent game production in historical and situated terms, as “woodshedding” in the interest of shaping “eloquent potential” for the end-user. The author draws on musical performance and jazz history to articulate a design methodology for independent game design, wherein tensions and constraints related to hardware and software limits, on one hand, and story and playability in reception, on the other, are resolved in the creation of a playable, expressive “story instrument.” The author describes the concrete challenges involved in designing games as an independent, explaining how initial enthusiasm for the Wii platform led to the choice of another gesturally oriented platform, the Apple iPhone, for a line of playable stories called “Opertoons.” (Adapted from the transcript of a lecture given at the University of California, Riverside)
Median Nerve Compression From a Nondisplaced Fracture of the Coronoid Process of the Ulna
Authors: Kent Jeremy B. , Barkdull Thad J. , Guidi Eric J.
Published: January 2010

Median nerve neuropathy following an elbow injury is uncommon. When it occurs, understanding the median nerve distribution and anatomy is crucial for identifying the cause and for distinguishing cases that can be managed with observation as opposed to intervention. The consequences of misdiagnosis can result in permanent disability. Understanding the mechanisms of nerve injury will help the clinician anticipate prognosis and guide treatment. Stretch, transection, and compression of nerves may present similarly, but isolating the mechanism and the extent of injury can guide the treatment modalities and help predict the overall recovery. The case is a report of median nerve compression in a woman after a nondisplaced fracture of the coronoid process of the ulna. Despite the unique nature of the patient’s symptoms, the neuropathy resolved with “watchful waiting.” The location of the injury was a key component in identifying the cause of the neuropathy. It highlights the importance of identifying a cause; some cases will resolve without intervention. Clinicians should consider median nerve compression when presented with a patient experiencing neurologic symptoms following such a fracture.
Long-term recovery after hematopoietic cell transplantation: predictors of quality-of-life concerns
Authors: Wong F. Lennie , Francisco Liton , Togawa Kayo , Bosworth Alysia , Gonzales Mitzi , Hanby Cara , Sabado Melanie , Grant Marcia , Forman Stephen J. , Bhatia Smita
Published: January 2010

This prospective longitudinal study examined the quality of life (QOL) after hematopoietic cell transplantation (HCT) and identified risk factors of poor QOL in 312 adult autologous and allogeneic HCT patients. Physical, psychological, social, and spiritual well-being was assessed before HCT, 6 months, and 1, 2, and 3 years after HCT. For all HCT patients, physical QOL was stable from before to after HCT (P > .05); psychologic (P < .001), social (P < .001), and spiritual (P = .03) QOL improved at 6 months. Study noncompleters (because of illness or death) had worse QOL. Allogeneic patients reported worse physical and psychologic well-being (P < .05). Older patients reported worse physical but better social well-being regardless of HCT type (P < .05). Two or more domains were affected by race/ethnicity, household income, and education in autologous patients, and by body mass index (BMI), decline in BMI, primary diagnosis, and chronic graft-versus-host disease (GVHD) in allogeneic patients (P < .05). At 3 years, 74% of HCT patients were employed full or part time. Older autologous patients with lower pre-HCT income were less likely to work (P < .05); allogeneic patients with chronic GVHD were less likely to work (P = .002). Multidisciplinary efforts to identify and support vulnerable subgroups after HCT need to be developed.
PI3K p110δ regulates T-cell cytokine production during primary and secondary immune responses in mice and humans
Authors: Soond Dalya R. , Bjørgo Elisa , Moltu Kristine , Dale Verity Q. , Patton Daniel T. , Torgersen Knut Martin , Galleway Fiona , Twomey Breda , Clark Jonathan , Gaston J. S. Hill , Taskén Kjetil , Bunyard Peter , Okkenhaug Klaus
Published: January 2010

We have previously described critical and nonredundant roles for the phosphoinositide 3-kinase p110δ during the activation and differentiation of naive T cells, and p110δ inhibitors are currently being developed for clinical use. However, to effectively treat established inflammatory or autoimmune diseases, it is important to be able to inhibit previously activated or memory T cells. In this study, using the isoform-selective inhibitor IC87114, we show that sustained p110δ activity is required for interferon-γ production. Moreover, acute inhibition of p110δ inhibits cytokine production and reduces hypersensitivity responses in mice. Whether p110δ played a similar role in human T cells was unknown. Here we show that IC87114 potently blocked T-cell receptor–induced phosphoinositide 3-kinase signaling by both naive and effector/memory human T cells. Importantly, IC87114 reduced cytokine production by memory T cells from healthy and allergic donors and from inflammatory arthritis patients. These studies establish that previously activated memory T cells are at least as sensitive to p110δ inhibition as naive T cells and show that mouse models accurately predict p110δ function in human T cells. There is therefore a strong rationale for p110δ inhibitors to be considered for therapeutic use in T-cell–mediated autoimmune and inflammatory diseases.
Stem cell transplantation in multiple myeloma: impact of response failure with thalidomide or lenalidomide induction
Authors: Gertz Morie A. , Kumar Shaji , Lacy Martha Q. , Dispenzieri Angela , Dingli David , Hayman Suzanne R. , Buadi Francis K. , Hogan William J.
Published: January 2010

Autologous stem cell transplantation as a platform for multiple myeloma treatment is the standard of care for patients who can safely withstand the procedure. Before novel agents were introduced, one-third to one-half of patients did not achieve partial response at transplantation. Previous medical literature has shown that in this past era, absence of initial response to induction therapy had no impact on progression-free survival and overall survival after high-dose therapy. Lack of response to initial induction did not preclude a good response after stem cell transplantation. With the introduction of novel agents—immunomodulatory drugs and proteasome inhibitors—response rates with initial therapy are now between 70% and 100%. This retrospective study analyzes progression-free survival and overall survival in patients who do not have a partial response (never responded or progressed during continuous therapy) after induction therapy with a regimen that contains thalidomide or lenalidomide. Unlike patients in reports published previously—before immunomodulatory drugs—patients who do not achieve partial remission have a significantly shorter overall survival from transplantation (73.5 vs 30.4 months) and a shorter progression-free survival (22.1 vs 13.1 months; P < .001). Absence of a response to induction therapy with thalidomide or lenalidomide predicts a poorer outcome after high-dose therapy.
The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure
Authors: Spellman Stephen , Bray Robert , Rosen-Bronson Sandra , Haagenson Michael , Klein John , Flesch Susan , Vierra-Green Cynthia , Anasetti Claudio
Published: January 2010

Donor-directed human leukocyte antigen (HLA)–specific allo-antibodies (DSAs) cause graft failure in animal models of hematopoietic stem cell transplantation (HCT). Archived pretransplantation sera from graft failure patients (n = 37) and a matched case-control cohort (n = 78) were tested to evaluate the role of DSAs in unrelated donor HCT. Controls were matched for disease, disease status, graft type, patient age, and transplantation year. Patients had acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome; 98% received myeloablative conditioning regimens 100% received T-replete grafts, 97% received marrow, 95% HLA-mismatched, and 97% received calcineurin-based graft-versus-host disease prophylaxis. Among the 37 failed transplantations, 9 (24%) recipients possessed DSAs against HLA-A, B, and/or DP, compared with only 1 (1%) of 78 controls. Therefore, the presence of DSAs was significantly associated with graft failure (odds ratio = 22.84; 95% confidence interval, 3.57-∞; P < .001). These results indicate that the presence of pretransplantation DSAs in recipients of unrelated donor HCT is associated with failed engraftment and should be considered in HCT donor selection.
SeqTrim: a high-throughput pipeline for pre-processing any type of sequence read
Authors: Falgueras Juan , Lara Antonio J , Fernández-Pozo Noé , Cantón Francisco R , Pérez-Trabado Guillermo , Claros M Gonzalo
Published: January 2010

Background

High-throughput automated sequencing has enabled an exponential growth rate of sequencing data. This requires increasing sequence quality and reliability in order to avoid database contamination with artefactual sequences. The arrival of pyrosequencing enhances this problem and necessitates customisable pre-processing algorithms.

Results

SeqTrim has been implemented both as a Web and as a standalone command line application. Already-published and newly-designed algorithms have been included to identify sequence inserts, to remove low quality, vector, adaptor, low complexity and contaminant sequences, and to detect chimeric reads. The availability of several input and output formats allows its inclusion in sequence processing workflows. Due to its specific algorithms, SeqTrim outperforms other pre-processors implemented as Web services or standalone applications. It performs equally well with sequences from EST libraries, SSH libraries, genomic DNA libraries and pyrosequencing reads and does not lead to over-trimming.

Conclusions

SeqTrim is an efficient pipeline designed for pre-processing of any type of sequence read, including next-generation sequencing. It is easily configurable and provides a friendly interface that allows users to know what happened with sequences at every pre-processing stage, and to verify pre-processing of an individual sequence if desired. The recommended pipeline reveals more information about each sequence than previously described pre-processors and can discard more sequencing or experimental artefacts.
The ADH1B Arg47His polymorphism in East Asian populations and expansion of rice domestication in history
Authors: Peng Yi , Shi Hong , Qi Xue-bin , Xiao Chun-jie , Zhong Hua , Ma Run-lin Z , Su Bing
Published: January 2010

Background

The emergence of agriculture about 10,000 years ago marks a dramatic change in human evolutionary history. The diet shift in agriculture societies might have a great impact on the genetic makeup of Neolithic human populations. The regionally restricted enrichment of the class I alcohol dehydrogenase sequence polymorphism (ADH1BArg47His) in southern China and the adjacent areas suggests Darwinian positive selection on this genetic locus during Neolithic time though the driving force is yet to be disclosed.

Results

We studied a total of 38 populations (2,275 individuals) including Han Chinese, Tibetan and other ethnic populations across China. The geographic distribution of the ADH1B*47His allele in these populations indicates a clear east-to-west cline, and it is dominant in south-eastern populations but rare in Tibetan populations. The molecular dating suggests that the emergence of the ADH1B*47His allele occurred about 10,000~7,000 years ago.

Conclusion

We present genetic evidence of selection on the ADH1BArg47His polymorphism caused by the emergence and expansion of rice domestication in East Asia. The geographic distribution of the ADH1B*47His allele in East Asia is consistent with the unearthed culture relic sites of rice domestication in China. The estimated origin time of ADH1B*47His allele in those populations coincides with the time of origin and expansion of Neolithic agriculture in southern China.
DIGAP - a Database of Improved Gene Annotation for Phytopathogens
Authors: Gao Na , Chen Ling-Ling , Ji Hong-Fang , Wang Wei , Chang Ji-Wei , Gao Bei , Zhang Lin , Zhang Shi-Cui , Zhang Hong-Yu
Published: January 2010

Background

Bacterial plant pathogens are very harmful to their host plants, which can cause devastating agricultural losses in the world. With the development of microbial genome sequencing, many strains of phytopathogens have been sequenced. However, some misannotations exist in these phytopathogen genomes. Our objective is to improve these annotations and store them in a central database DIGAP.

Description

DIGAP includes the following improved information on phytopathogen genomes. (i) All the 'hypothetical proteins' were checked, and non-coding ORFs recognized by the Z curve method were removed. (ii) The translation initiation sites (TISs) of 20% ~ 25% of all the protein-coding genes have been corrected based on the NCBI RefSeq, ProTISA database and an ab initio program, GS-Finder. (iii) Potential functions of about 10% 'hypothetical proteins' have been predicted using sequence alignment tools. (iv) Two theoretical gene expression indices, the codon adaptation index (CAI) and the E(g) index, were calculated to predict the gene expression levels. (v) Potential agricultural bactericide targets and their homology-modeled 3D structures are provided in the database, which is of significance for agricultural antibiotic discovery.

Conclusion

The results in DIGAP provide useful information for understanding the pathogenetic mechanisms of phytopathogens and for finding agricultural bactericides. DIGAP is freely available at http://ibi.hzau.edu.cn/digap/.
Persistent, triple-virus co-infections in mosquito cells
Authors: Kanthong Nipaporn , Khemnu Nuanpan , Pattanakitsakul Sa-Nga , Malasit Prida , Flegel Timothy W
Published: January 2010

Background

It is known that insects and crustaceans can carry simultaneous, active infections of two or more viruses without showing signs of disease, but it was not clear whether co-infecting viruses occupied the same cells or different cells in common target tissues. Our previous work showed that successive challenge of mosquito cell cultures followed by serial, split-passage resulted in stabilized cultures with 100% of the cells co-infected with Dengue virus (DEN) and an insect parvovirus (densovirus) (DNV). By addition of Japanese encephalitis virus (JE), we tested our hypothesis that stable, persistent, triple-virus co-infections could be obtained by the same process.

Results

Using immunocytochemistry by confocal microscopy, we found that JE super-challenge of cells dually infected with DEN and DNV resulted in stable cultures without signs of cytopathology, and with 99% of the cells producing antigens of the 3 viruses. Location of antigens for all 3 viruses in the triple co-infections was dominant in the cell nuclei. Except for DNV, this differed from the distribution in cells persistently infected with the individual viruses or co-infected with DNV and DEN. The dependence of viral antigen distribution on single infection or co-infection status suggested that host cells underwent an adaptive process to accommodate 2 or more viruses.

Conclusions

Individual mosquito cells can accommodate at least 3 viruses simultaneously in an adaptive manner. The phenomenon provides an opportunity for genetic exchange between diverse viruses and it may have important medical and veterinary implications for arboviruses.
Bicarbonate enhances expression of the endocarditis and biofilm associated pilus locus, ebpR-ebpABC, in Enterococcus faecalis
Authors: Bourgogne Agathe , Thomson L Charlene , Murray Barbara E
Published: January 2010

Background

We previously identified ebpR, encoding a potential member of the AtxA/Mga transcriptional regulator family, and showed that it is important for transcriptional activation of the Enterococcus faecalis
e ndocarditis and b iofilm associated p ilus operon, ebpABC. Although ebpR is not absolutely essential for ebpABC expression (100-fold reduction), its deletion led to phenotypes similar to those of an ebpABC mutant such as absence of pili at the cell surface and, consequently, reduced biofilm formation. A non-piliated ebpABC mutant has been shown to be attenuated in a rat model of endocarditis and in a murine urinary tract infection model, indicating an important participation of the ebpR-ebpABC locus in virulence. However, there is no report relating to the environmental conditions that affect expression of the ebpR-ebpABC locus.

Results

In this study, we examined the effect of CO2/HCO3
-, pH, and the Fsr system on the ebpR-ebpABC locus expression. The presence of 5% CO2/0.1 M HCO3
- increased ebpR-ebpABC expression, while the Fsr system was confirmed to be a weak repressor of this locus. The mechanism by which the Fsr system repressed the ebpR-ebpABC locus expression appears independent of the effects of CO2
- bicarbonate. Furthermore, by using an ebpA::lacZ fusion as a reporter, we showed that addition of 0.1 M sodium bicarbonate to TSBG (buffered at pH 7.5), but not the presence of 5% CO2, induced ebpA expression in TSBG broth. In addition, using microarray analysis, we found 73 genes affected by the presence of sodium bicarbonate (abs(fold) > 2, P < 0.05), the majority of which belong to the PTS system and ABC transporter families. Finally, pilus production correlated with ebpA mRNA levels under the conditions tested.

Conclusions

This study reports that the ebp locus expression is enhanced by the presence of bicarbonate with a consequential increase in the number of cells producing pili. Although the molecular basis of the bicarbonate effect remains unclear, the pathway is independent of the Fsr system. In conclusion, E. faecalis joins the growing family of pathogens that regulates virulence gene expression in response to bicarbonate and/or CO2.
miR-21: an oncomir on strike in prostate cancer
Authors: Folini Marco , Gandellini Paolo , Longoni Nicole , Profumo Valentina , Callari Maurizio , Pennati Marzia , Colecchia Maurizio , Supino Rosanna , Veneroni Silvia , Salvioni Roberto , Valdagni Riccardo , Daidone Maria Grazia , Zaffaroni Nadia
Published: January 2010

Background

Aberrant expression of microRNAs, small non-coding RNA molecules that post-transcriptionally repress gene expression, seems to be causatively linked to the pathogenesis of cancer. In this context, miR-21 was found to be overexpressed in different human cancers (e.g. glioblastoma, breast cancer). In addition, it is thought to be endowed with oncogenic properties due to its ability to negatively modulate the expression of tumor-suppressor genes (e.g. PTEN) and to cause the reversion of malignant phenotype when knocked- down in several tumor models. On the basis of these findings, miR-21 has been proposed as a widely exploitable cancer-related target. However, scanty information is available concerning the relevance of miR-21 for prostate cancer. In the present study, we investigated the role of miR-21 and its potential as a therapeutic target in two prostate cancer cell lines, characterized by different miR-21 expression levels and PTEN gene status.

Results

We provide evidence that miR-21 knockdown in prostate cancer cells is not sufficient per se i) to affect the proliferative and invasive potential or the chemo- and radiosensitivity profiles or ii) to modulate the expression of the tumor-suppressors PTEN and Pdcd4, which in other tumor types were found to be regulated by miR-21. We also show that miR-21 is not differently expressed in carcinomas and matched normal tissues obtained from 36 untreated prostate cancer patients subjected to radical prostatectomy.

Conclusions

Overall, our data suggest that miR-21 is not a central player in the onset of prostate cancer and that its single hitting is not a valuable therapeutic strategy in the disease. This supports the notion that the oncogenic properties of miR-21 could be cell and tissue dependent and that the potential role of a given miRNA as a therapeutic target should be contextualized with respect to the disease.
Ruling out coronary heart disease in primary care patients with chest pain: a clinical prediction score
Authors: Gencer Baris , Vaucher Paul , Herzig Lilli , Verdon François , Ruffieux Christiane , Bösner Stefan , Burnand Bernard , Bischoff Thomas , Donner-Banzhoff Norbert , Favrat Bernard
Published: January 2010

Background

Chest pain raises concern for the possibility of coronary heart disease. Scoring methods have been developed to identify coronary heart disease in emergency settings, but not in primary care.

Methods

Data were collected from a multicenter Swiss clinical cohort study including 672 consecutive patients with chest pain, who had visited one of 59 family practitioners' offices. Using delayed diagnosis we derived a prediction rule to rule out coronary heart disease by means of a logistic regression model. Known cardiovascular risk factors, pain characteristics, and physical signs associated with coronary heart disease were explored to develop a clinical score. Patients diagnosed with angina or acute myocardial infarction within the year following their initial visit comprised the coronary heart disease group.

Results

The coronary heart disease score was derived from eight variables: age, gender, duration of chest pain from 1 to 60 minutes, substernal chest pain location, pain increasing with exertion, absence of tenderness point at palpation, cardiovascular risks factors, and personal history of cardiovascular disease. Area under the receiver operating characteristics curve was of 0.95 with a 95% confidence interval of 0.92; 0.97. From this score, 413 patients were considered as low risk for values of percentile 5 of the coronary heart disease patients. Internal validity was confirmed by bootstrapping. External validation using data from a German cohort (Marburg, n = 774) revealed a receiver operating characteristics curve of 0.75 (95% confidence interval, 0.72; 0.81) with a sensitivity of 85.6% and a specificity of 47.2%.

Conclusions

This score, based only on history and physical examination, is a complementary tool for ruling out coronary heart disease in primary care patients complaining of chest pain.
Down-Regulation of Toll-Like Receptor 4 Gene Expression by Short Interfering RNA Attenuates Bone Cancer Pain in a Rat Model
Authors: Lan Liu Si , Ping Yang Jian , Na Wang Li , Miao Jiang , Cheng Qiu Qiao , Ni Ma Zhen , Lei Liu , Fang Li Cai , Guang Ren Chun , Jin Zhou , Wei Li
Published: January 2010

Background:

This study demonstrates a critical role in CNS innate immunity of the microglial Toll-like receptor 4 (TLR4) in the induction and maintenance of behavioral hypersensitivity in a rat model of bone cancer pain with the technique of RNA interference (RNAi). We hypothesized that after intramedullary injection of Walker 256 cells (a breast cancer cell line) into the tibia, CNS neuroimmune activation and subsequent cytokine expression are triggered by the stimulation of microglial membrane-bound TLR4.

Results:

We assessed tactile allodynia and spontaneous pain in female Sprague-Dawley (SD) rats after intramedullary injection of Walker 256 cells into the tibia. In a complementary study, TLR4 small interfering RNA (siRNA) was administered intrathecally to bone cancer pain rats to reduce the expression of spinal TLR4. The bone cancer pain rats treated with TLR4 siRNA displayed significantly attenuated behavioral hypersensitivity and decreased expression of spinal microglial markers and proinflammatory cytokines compared with controls. Only intrathecal injection of TRL4 siRNA at post-inoculation day 4 could prevent initial development of bone cancer pain; intrathecal injection of TRL4 siRNA at post-inoculation day 9 could attenuate, but not completely block, well-established bone cancer pain.

Conclusions:

TLR4 might be the main mediator in the induction of bone cancer pain. Further study of this early, specific, and innate CNS/microglial response, and how it leads to sustained glial/neuronal hypersensitivity, might lead to new therapies for the prevention and treatment of bone cancer pain syndromes.
Effects of Parecoxib and Fentanyl on Nociception-Induced Cortical Activity
Authors: Peng Yuan-Zhi , Li Xiao-Xi , Wang Ying-Wei
Published: January 2010

Background:

Analgesics, including opioids and non-steroid anti-inflammatory drugs reduce postoperative pain. However, little is known about the quantitative effects of these drugs on cortical activity induced by nociceptive stimulation. The aim of the present study was to determine the neural activity in response to a nociceptive stimulus and to investigate the effects of fentanyl (an opioid agonist) and parecoxib (a selective cyclooxygenase-2 inhibitor) on this nociception-induced cortical activity evoked by tail pinch. Extracellular recordings (electroencephalogram and multi-unit signals) were performed in the area of the anterior cingulate cortex while intracellular recordings were made in the primary somatosensory cortex. The effects of parecoxib and fentanyl on induced cortical activity were compared.

Results:

Peripheral nociceptive stimulation in anesthetized rats produced an immediate electroencephalogram (EEG) desynchronization resembling the cortical arousal (low-amplitude, fast-wave activity), while the membrane potential switched into a persistent depolarization state. The induced cortical activity was abolished by fentanyl, and the fentanyl's effect was reversed by the opioid receptor antagonist, naloxone. Parecoxib, on the other hand, did not significantly affect the neural activity.

Conclusion:

Cortical activity was modulated by nociceptive stimulation in anesthetized rats. Fentanyl showed a strong inhibitory effect on the nociceptive-stimulus induced cortical activity while parecoxib had no significant effect.
The Roles of iPLA2, TRPM8 and TRPA1 in Chemically Induced Cold Hypersensitivity
Authors: Gentry Clive , Stoakley Natalie , Andersson David A , Bevan Stuart
Published: January 2010

Background:

The cooling agents menthol and icilin act as agonists at TRPM8 and TRPA1. In vitro, activation of TRPM8 by icilin and cold, but not menthol, is dependent on the activity of a sub-type of phospholipase A2, iPLA2. Lysophospholipids (e.g. LPC) produced by PLA2 activity can also activate TRPM8. The role of TRPA1 as a primary cold sensor in vitro is controversial, although there is evidence that TRPA1 plays a role in behavioural responses to noxious cold stimuli. In this study, we have investigated the roles of TRPM8 and TRPA1 and the influence of iPLA2 on noxious cold sensitivities in naïve animals and after local administration of menthol, icilin and LPC. The roles of the channels in cold sensitivity were investigated in mice lacking either TRPM8 ( Trpm8−/−) or TRPA1 ( Trpa1−/−).

Results:

Intraplantar administration of icilin evoked a dose-dependent increase in sensitivity to a 10°C stimulus that was inhibited by iPLA2 inhibition with BEL. In contrast the cold hypersensitivities elicited by intraplantar menthol and LPC were not inhibited by BEL treatment. BEL had no effect on basal cold sensitivity and mechanical hypersensitivities induced by the TRPV1 agonist, capsaicin, and the P2X3 agonist α,β-methylene ATP. Both Trpm8−/− and Trpa1−/− mice showed longer latencies for paw withdrawal from a 10°C stimulus than wild-type littermates. Cold hypersensitivities induced by either icilin or LPC were absent in Trpm8−/− mice but were retained in Trpa1−/− mice. In contrast, cold hypersensitivity evoked by menthol was present in Trpm8−/− mice but was lost in Trpa1−/− mice.

Conclusions:

The findings that iPLA2 inhibition blocked the development of cold hypersensitivity after administration of icilin but failed to affect menthol-induced hypersensitivity agree well with our earlier in vitro data showing a differential effect of iPLA2 inhibition on the agonist activities of these agents. The ability of LPC to induce cold hypersensitivity supports a role for iPLA2 in modulating TRPM8 activity in vivo. Studies on genetically modified mice demonstrated that the effects of icilin and LPC were mediated by TRPM8 and not TRPA1. In contrast, menthol-induced cold hypersensitivity was dependent on expression of TRPA1 and not TRPM8.
Regulation of AMPA Receptors in Spinal Nociception
Authors: Wang Yun , Wu Jing , Wu Zhiguo , Lin Qing , Yue Yun , Fang Li
Published: January 2010

The functional properties of α-amino-3-hydroxy-5-methy-4-isoxazole propionate (AMPA) receptors in different brain regions, such as hippocampus and cerebellum, have been well studied in vitro and in vivo. The AMPA receptors present a unique characteristic in the mechanisms of subunit regulation during LTP (long-term potentiation) and LTD (long-term depression), which are involved in the trafficking, altered composition and phosphorylation of AMPA receptor subunits. Accumulated data have demonstrated that spinal AMPA receptors play a critical role in the mechanism of both acute and persistent pain. However, less is known about the biochemical regulation of AMPA receptor subunits in the spinal cord in response to painful stimuli. Recent studies have shown that some important regulatory processes, such as the trafficking of AMPA receptor subunit, subunit compositional changes, phosphorylation of AMPA receptor subunits, and their interaction with partner proteins may contribute to spinal nociceptive transmission. Of all these regulation processes, the phosphorylation of AMPA receptor subunits is the most important since it may trigger or affect other cellular processes. Therefore, these study results may suggest an effective strategy in developing novel analgesics targeting AMPA receptor subunit regulation that may be useful in treating persistent and chronic pain without unacceptable side effects in the clinics.
Pyk2 uncouples metabotropic glutamate receptor G protein signaling but facilitates ERK1/2 activation
Authors: Nicodemo Alexander A , Pampillo Macarena , Ferreira Lucimar T , Dale Lianne B , Cregan Tamara , Ribeiro Fabiola M , Ferguson Stephen SG
Published: January 2010

Group I metabotropic glutamate receptors (mGluRs) are coupled via Gαq/11 to the activation of phospholipase Cβ, which hydrolyzes membrane phospholipids to form inositol 1,4,5 trisphosphate and diacylglycerol. This results in the release of Ca2+ from intracellular stores and the activation of protein kinase C. The activation of Group I mGluRs also results in ERK1/2 phosphorylation. We show here, that the proline-rich tyrosine kinase 2 (Pyk2) interacts with both mGluR1 and mGluR5 and is precipitated with both receptors from rat brain. Pyk2 also interacts with GST-fusion proteins corresponding to the second intracellular loop and the distal carboxyl-terminal tail domains of mGluR1a. Pyk2 colocalizes with mGluR1a at the plasma membrane in human embryonic kidney (HEK293) cells and with endogenous mGluR5 in cortical neurons. Pyk2 overexpression in HEK293 results in attenuated basal and agonist-stimulated inositol phosphate formation in mGluR1 expressing cells and involves a mechanism whereby Pyk2 displaces Gαq/11 from the receptor. The activation of endogenous mGluR1 in primary mouse cortical neuron stimulates ERK1/2 phosphorylation. Treatments that prevent Pyk2 phosphorylation in cortical neurons, and the overexpression of Pyk2 dominant-negative and catalytically inactive Pyk2 mutants in HEK293 cells, prevent ERK1/2 phosphorylation. The Pyk2 mediated activation of ERK1/2 phosphorylation is also Src-, calmodulin- and protein kinase C-dependent. Our data reveal that Pyk2 couples the activation mGluRs to the mitogen-activated protein kinase pathway even though it attenuates mGluR1-dependent G protein signaling.
Ultrastaging of lymph node in uterine cancers
Authors: Bézu Corinne , Coutant Charles , Ballester Marcos , Feron Jean-Guillaume , Rouzier Roman , Uzan Serge , Daraï Emile
Published: January 2010

Background

Lymph node status is an important prognostic factor and a criterion for adjuvant therapy in uterine cancers. While detection of micrometastases by ultrastaging techniques is correlated to prognosis in several other cancers, this remains a matter of debate for uterine cancers. The objective of this review on sentinel nodes (SN) in uterine cancers was to determine the contribution of ultrastaging to detect micrometastases.

Methods

Review of the English literature on SN procedure in cervical and endometrial cancers and histological techniques including hematoxylin and eosin (H&E) staining, serial sectioning, immunohistochemistry (IHC) and molecular techniques to detect micrometastases.

Results

In both cervical and endometrial cancers, H&E and IHC appeared insufficient to detect micrometastases. In cervical cancer, using H&E, serial sectioning and IHC, the rate of macrometastases varied between 7.1% and 36.3% with a mean value of 25.8%. The percentage of women with micrometastases ranged from 0% and 47.4% with a mean value of 28.3%. In endometrial cancer, the rate of macrometastases varied from 0% to 22%. Using H&E, serial sectioning and IHC, the rate of micrometastases varied from 0% to 15% with a mean value of 5.8%. In both cervical and endometrial cancers, data on the contribution of molecular techniques to detect micrometastases are insufficient to clarify their role in SN ultrastaging.

Conclusion

In uterine cancers, H&E, serial sectioning and IHC appears the best histological combined technique to detect micrometastases. Although accumulating data have proved the relation between the risk of recurrence and the presence of micrometastases, their clinical implications on indications for adjuvant therapy has to be clarified.
MALT lymphoma of the rectum, presenting with rectal prolapsus: a case report
Authors: Ersoz Feyzullah , Toros Ahmet Burak , Bektas Hasan , Ozcan Ozhan , Koc Oguz , Arikan Soykan
Published: January 2010

Up to now, there have been only a few reported cases of Mucosa-associated lymphoid tissue (MALT) lymphomas arising in the rectum. Its clinical presentation is indistinguishable from that of rectal carcinoma but the treatment is apparently different. Symptoms of primary lymphomas involving the rectum include; anorexia, weight loss, change in bowel habits, obstruction, and bleeding. These symptoms are not disease specific and can be seen in many other gastrointestinal disorders. Patients with polypoid masses may present with obstruction symptoms. In this rare case, a female patient admitted to the emergency service with prolapsus of a rectal mass.

The optimal treatment of rectal MALT lymphoma is not well defined yet, given the rarity of the disease. Surgical resection of the localized lesion and following adjuvant chemotherapy has proved to be an effective treatment option. However, a close and long-lasting follow-up is important.
Cellular zinc homeostasis is a regulator in monocyte differentiation of HL-60 cells by 1α,25-dihydroxyvitamin D3
Authors: Dubben Svenja , Hönscheid Andrea , Winkler Katja , Rink Lothar , Haase Hajo
Published: January 2010

A decrease of free cellular zinc promotes monocyte differentiation of HL-60 cells by alleviating zinc-mediated inhibition of adenylate cyclase.

It was reported previously that zinc-deficient mice show impaired lymphopoiesis. At the same time, monocyte numbers in these animals are increased, indicating a negative impact of zinc on monocyte development. Here, we investigate the role of zinc homeostasis in the differentiation of myeloid precursors into monocytes. Reduced gene expression of several zinc transporters, predominantly from the Zip family, was observed during 1α, 25-dihydroxyvitamin D3 (1,25D3)-induced differentiation of HL-60 cells. This was accompanied by a reduction of intracellular-free zinc, measured by FluoZin-3. Amplifying this reduction with the zinc chelator TPEN or zinc-depleted cell-culture medium enhanced 1,25D3-induced expression of monocytic surface markers CD11b and CD14 on HL-60, THP-1, and NB4 cells. In contrast, differentiation of NB4 cells to granulocytes was not zinc-sensitive, pointing toward a specific effect of zinc on monocyte differentiation. Further, monocyte functions, such as TNF-α secretion, phagocytosis, and oxidative burst, were also augmented by differentiation in the presence of TPEN. The second messenger cAMP promotes monocyte differentiation. We could show that zinc inhibits the cAMP-synthesizing enzyme adenylate cyclase, and chelation of zinc by TPEN increases cAMP generation after stimulation with the adenylate cyclase activator forskolin. Based on our in vitro results and the in vivo observations from the literature, we suggest a model in which the intracellular-free zinc concentration limits AC activity, and the decrease of zinc after 1,25D3 treatment promotes differentiation by relieving AC inhibition. Thus, cellular zinc homeostasis acts as an endogenous modulator of monocyte differentiation.
CFTR-mediated halide transport in phagosomes of human neutrophils
Authors: Painter Richard G , Marrero Luis , Lombard Gisele A , Valentine Vincent G , Nauseef William M , Wang Guoshun
Published: January 2010

CFTR transports chloride anions necessary for HOCl production and optimal microbicidal activity in human neutrophil phagosomes.

Chloride serves as a critical component of innate host defense against infection, providing the substrate for MPO-catalyzed production of HOCl in the phagosome of human neutrophils. Here, we used halide-specific fluorescent sensors covalently coupled to zymosan particles to investigate the kinetics of chloride and iodide transport in phagosomes of human neutrophils. Using the self-ratioable fluorescent probe specific for chloride anion, we measured chloride dynamics within phagosomes in response to extracellular chloride changes by quantitative fluorescence microscopy. Under the experimental conditions used, normal neutrophils showed rapid phagosomal chloride uptake with an initial influx rate of 0.31 ± 0.04 mM/s (n=5). GlyH-101, a CFTRinh, decreased the rate of uptake in a dose-dependent manner. Neutrophils isolated from CF patients showed a significantly slower rate of chloride uptake by phagosomes, having an initial influx rate of 0.043 ± 0.012 mM/s (n=5). Interestingly, the steady-state level of chloride in CF phagosomes was ∼26 mM, significantly lower than that of the control (∼68 mM). As CFTR transports chloride as well as other halides, we conjugated an iodide-sensitive probe as an independent approach to confirm the results. The dynamics of iodide uptake by neutrophil phagosomes were monitored by flow cytometry. CFTRinh172 blocked 40–50% of the overall iodide uptake by phagosomes in normal neutrophils. In a parallel manner, the level of iodide uptake by CF phagosomes was only 20–30% of that of the control. Taken together, these results implicate CFTR in transporting halides into the phagosomal lumen.
Utility of Various Functional and Anatomic Imaging Modalities for Detection of Ectopic Adrenocorticotropin-Secreting Tumors
Authors: Zemskova Marina S. , Gundabolu Bhaskar , Sinaii Ninet , Chen Clara C. , Carrasquillo Jorge A. , Whatley Millie , Chowdhury Iffat , Gharib Ahmed M. , Nieman Lynnette K.
Published: January 2010

Context: Because ectopic ACTH-secreting (EAS) tumors are often occult, improved imaging is needed.

Objective: Our objective was to evaluate the utility of [111In-DTPA-d-Phe]pentetreotide scintigraphy [octreotide (OCT)] imaging at 6 mCi [low OCT (LOCT)] and 18 mCi [high OCT (HOCT)], [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) and [18F]l-3,4-dihydroxyphenylalanine (F-DOPA)-PET scans, computed tomography (CT), and magnetic resonance imaging (MRI).

Design and Setting: The study was a prospective evaluation at a clinical research center.

Patients: Forty-one subjects participated, 30 (17 female) with resected EAS tumors and 11 (three female) with occult EAS, based on inferior petrosal sinus sampling results and imaging studies.

Intervention: Intervention included CT and MRI of neck, chest, abdomen, LOCT (with or without HOCT) and FDG- or F-DOPA-PET without CT every 6–12 months.

Main Outcome Measure: Tumor identification was the main outcome measure.

Results: Most recent results were analyzed. Eighteen patients had tumor resected on the first visit; otherwise, surgery occurred 33 ± 25 (9–99) months later. Tumor size was 1.9 ± 1.7 (0.8–8.0) cm; 83% were intrathoracic. CT, MRI, LOCT, HOCT, FDG-PET, and F-DOPA-PET had sensitivities per patient of 93% [95% confidence interval (CI) = 79–98%], 90% (95% CI = 74–96%), 57% (95% CI = 39–73%), 50% (95% CI = 25–75%), 64% (95% CI = 35–85%), and 55% (95% CI = 28–79%) and positive predictive values (PPV) per lesion of 66, 74, 79, 89, 53, and 100%, respectively. LOCT and PET detected only lesions seen by CT/MRI; abnormal LOCT or F-DOPA-PET improved PPV of CT/MRI. By modality, the fraction of patients with one or more false-positive findings was 50% by CT, 31% by MRI, 18% by L/HOCT, and 18% by FDG-PET. Eight occult EAS patients had 64 ± 58 (9–198) months follow-up; others had none.

Conclusions: High sensitivity and PPV suggest thoracic CT/MRI plus LOCT scans for initial imaging, with lesion confirmation by two modalities.
Dialect Boundaries in New Jersey
Authors: Coye Dale F.
Published: January 2010

This article uses a questionnaire to examine phonological, lexical, and grammatical forms that earlier studies identified as markers of dialect distinctions in New Jersey to ascertain whether the boundaries have changed for the youngest generation of speakers. The questionnaire was given to college students and mailed to high schools around the state for completion by college-bound seniors. Results indicate that in some cases the dialect differences more or less match those in existence for many generations, with a north-south division clearly evident. In other instances, the influence of New York City is evident, with variables decreasing in frequency as distance from the city increases. In still other cases, older statewide forms are disappearing, supplanted by variants found more typically outside of the East Coast.