bluuebunny/crossref_metadata_2025 huggingface dataset:
Smarter elder care? A cost-effectiveness analysis of implementing technology in elder care
Authors: Aanesen Margrethe , Lotherington Ann Therese , Olsen Frank
Published: September 2011

Whereas in most sectors, technology has taken over trivial and labour consuming tasks, this transformation has been delayed in the healthcare sector. Although appropriate technology is available, there is general resistance to substituting ‘warm’ hands with ‘cold’ technology. In the future, this may change as the number of elderly people increases relative to the people in the work force. In combination with an increasing demand for healthcare services, there are calls for efforts to increase productivity in the sector. Based on experience data from previous studies on information and communication technology efforts in the healthcare sector, we quantitatively assess the use of smart house technology and video visits in home care. Having identified healthcare providers, hospitals and relatives as the main affected groups, we show that smart house technology is cost-effective, even if only relatives gain from it. Video visits, which have higher implementation costs, demand effects on both relatives and health care providers in order to be a cost-effective tool in home care. As the analysis is purely quantitative, these results need to be complemented with qualitative effects and with more thorough discussions of the ethical, medical and legal aspects of the use of technology in home care.
Designing a web-based learning portal for geographic visualization and analysis in public health
Authors: Robinson Anthony C. , MacEachren Alan M. , Roth Robert E.
Published: September 2011

Interactive mapping and spatial analysis tools are under-utilized by health researchers and decision-makers as a result of scarce training materials, few examples demonstrating the successful use of geographic visualization, and poor mechanisms for sharing results generated by geovisualization. Here, we report on the development of the Geovisual EXplication(G-EX) Portal, a web-based application designed to connect researchers in geovisualization and related mapping sciences, to users who are working in public health and epidemiology. This paper focuses on the design and development of the G-EX Portal Learn module, a set of tools intended to disseminate learning artifacts. Initial design and development of the G-EX Portal has been guided by our past research on the use and usability of geovisualization in public health. As part of the iterative design and development process, we conducted a needs assessment survey with targeted end-users, which we report on here. The survey focused on users’ current learning habits, their preferred kind of learning artifacts and issues they may have with contributing learning artifacts to web portals. Survey results showed that users desire a diverse set of learning artifacts in terms of both formats and topics covered. Results also revealed a willingness of users to contribute both learning artifacts and personal information that would help other users to evaluate the credibility of the learning artifact source. We include a detailed description of the G-EX Portal Learn module and focus on modifications to the design of the Learn module as a result from feedback we received from our survey.
Making Sense Under a Midnight Sun
Authors: Schoen Steven W. , Spangler David S.
Published: September 2011

This essay analyzes the sense-making practices at work in directing a Russian–American youth arts program that included 2 weeks in Russia, and the production of a documentary film about that program. Both the filmmaker and the transdisciplinary art program director examine together their efforts to make sense of the event as their expectations for it collapse. We explore ways the creative practices of our disciplines shape our sense making and structure how we understand success, failure, and art. We trace how our experience both eludes sense and makes sense, and seek to reflect the provisional, incomplete, and emergent status of both our collaboration and our experiences of sense making. We struggle with the impulse that knowledge must be tamed and stabilized by narrative to be theoretically productive, and we suggest that the processes of thoughtfully and creatively contextualizing lived experiences have knowledge-value that exceeds the “success” or “failure” of their expression in conventional forms.
Psychiatric comorbidities in women with Celiac Disease
Authors: Arigo Danielle , Anskis Alicia M , Smyth Joshua M
Published: September 2011

Objective: Although the physical consequences of Celiac Disease are well studied, less is known about co-occurring psychiatric symptoms. This study examines psychiatric risk and comorbidities of women with Celiac Disease, who may be at increased risk for psychiatric symptoms (e.g. depression, and disordered eating behaviours).

Methods: Women ( N = 177) with Celiac Disease responded to an extensive web-mediated survey assessing dietary compliance, illness symptoms, psychiatric functioning, and disordered eating.

Results: Despite high reported dietary compliance, patients reported marked illness symptoms and impaired quality of life. A substantial minority endorsed symptoms that met criteria for the diagnosis of psychiatric disorders: 37% ( n = 65) met the threshold suggesting depression, and 22% ( n = 39) for disordered eating. Participants whose symptoms exceeded these clinical thresholds reported greater perceived stress and reduced overall mental health, relative to women below the clinical cutoffs.

Conclusions: Despite largely adhering to a gluten-free diet, a substantial subset of women with Celiac Disease report clinically relevant symptoms of depression and disordered eating; such symptoms are associated with increased psychosocial distress in other domains. These results suggest potential to improve the patient well-being through attention to psychosocial care, in addition to existing dietary recommendations for individuals with Celiac Disease.
Correlates of Party, Ideology and Issue Based Extremity in an era of Egocentric Publics
Authors: Wojcieszak Magdalena , Rojas Hernando
Published: September 2011

We extend the study of political extremity to an evolving media landscape. We differentiate between political and non-political uses of both “traditional” and “new” media, and situate political extremity within a new conceptualization of public– egocentric publics –a meso-level phenomenon enabled by new communication technologies that overcomes the traditional dichotomy of small groups and mass publics. Testing the relationship between information, expression, and extremity in Colombia, a sociopolitical context with high levels of polarization and distrust, we find that traditional media use is mostly unrelated to the tested forms of extremity: party-, ideology-, or issue-based. In turn, expressive Internet use is related to extremity and—contrary to what some commentators have feared—this relationship is negative. Lower extremity associated with online expression is consistent with the notion of egocentric publics advanced in this article. The results underscore the importance of differentiating between various media formats in political communication research, reveal the media correlates of various forms of extremity can take, and provide evidence that the emerging publics made possible by new media are not necessarily polarizing.
Different Practices, Similar Logic
Authors: Reich Zvi
Published: September 2011

This article seeks to explore whether political reporters present more meticulous, complex, and active standards of news reporting—justifying their special role as enablers of informed citizenry—and to help resolve the theoretical ambiguity regarding news beats as distinct domains of practice. The sample comprised reporters from three beat clusters—political, financial, and territorial—in nine national Israeli news organizations, who were asked to describe, source by source, how they obtained a sample of their recently published items ( N = 840), addressing sourcing patterns, news practices, and communication technologies used. As expected, reporting was found to be distinctive across beat clusters, with political reporters employing significantly and consistently higher standards although financial reporters, in contrast to expectations, were not found to be the weakest link in the reporting chain. Despite the substantial differences, the studied beats embody a united community of practice following a similar media logic.
Hierarchical Parallelization of Gene Differential Association Analysis
Authors: Needham Mark , Hu Rui , Dwarkadas Sandhya , Qiu Xing
Published: September 2011

Background

Microarray gene differential expression analysis is a widely used technique that deals with high dimensional data and is computationally intensive for permutation-based procedures. Microarray gene differential association analysis is even more computationally demanding and must take advantage of multicore computing technology, which is the driving force behind increasing compute power in recent years. In this paper, we present a two-layer hierarchical parallel implementation of gene differential association analysis. It takes advantage of both fine- and coarse-grain (with granularity defined by the frequency of communication) parallelism in order to effectively leverage the non-uniform nature of parallel processing available in the cutting-edge systems of today.

Results

Our results show that this hierarchical strategy matches data sharing behavior to the properties of the underlying hardware, thereby reducing the memory and bandwidth needs of the application. The resulting improved efficiency reduces computation time and allows the gene differential association analysis code to scale its execution with the number of processors. The code and biological data used in this study are downloadable from http://www.urmc.rochester.edu/biostat/people/faculty/hu.cfm

Conclusions

The performance sweet spot occurs when using a number of threads per MPI process that allows the working sets of the corresponding MPI processes running on the multicore to fit within the machine cache. Hence, we suggest that practitioners follow this principle in selecting the appropriate number of MPI processes and threads within each MPI process for their cluster configurations. We believe that the principles of this hierarchical approach to parallelization can be utilized in the parallelization of other computationally demanding kernels.
Genomic insights into an obligate epibiotic bacterial predator: Micavibrio aeruginosavorus ARL-13
Authors: Wang Zhang , Kadouri Daniel E , Wu Martin
Published: September 2011

Background

Although bacterial predators play important roles in the dynamics of natural microbial communities, little is known about the molecular mechanism of bacterial predation and the evolution of diverse predatory lifestyles.

Results

We determined the complete genome sequence of Micavibrio aeruginosavorus ARL-13, an obligate bacterial predator that feeds by "leeching" externally to its prey. Despite being an obligate predator depending on prey for replication, M. aeruginosavorus encodes almost all major metabolic pathways. However, our genome analysis suggests that there are multiple amino acids that it can neither make nor import directly from the environment, thus providing a simple explanation for its strict dependence on prey. Remarkably, despite apparent genome reduction, there is a massive expansion of genomic islands of foreign origin. At least nine genomic islands encode many genes that are likely important for Micavibrio-prey interaction such as hemolysin-related proteins. RNA-Seq analysis shows substantial transcriptome differences between the attack phase, when M. aeruginosavorus seeks its prey, and the attachment phase, when it feeds and multiplies. Housekeeping genes as well as genes involved in protein secretion were all dramatically up-regulated in the attachment phase. In contrast, genes involved in chemotaxis and flagellum biosynthesis were highly expressed in the attack phase but were shut down in the attachment phase. Our transcriptomic analysis identified additional genes likely important in Micavibrio predation, including porins, pilins and many hypothetical genes.

Conclusions

The findings from our phylogenomic and transcriptomic analyses shed new light on the biology and evolution of the epibiotic predatory lifestyle of M. aeruginosavorus. The analysis reported here and the availability of the complete genome sequence should catalyze future studies of this organism.
Cytoplasmic p21 is a potential predictor for cisplatin sensitivity in ovarian cancer
Authors: Xia Xi , Ma Quanfu , Li Xiao , Ji Teng , Chen Pingbo , Xu Hongbin , Li Kezhen , Fang Yong , Weng Danhui , Weng Yanjie , Liao Shujie , Han Zhiqiang , Liu Ronghua , Zhu Tao , Wang Shixuan , Xu Gang , Meng Li , Zhou Jianfeng , Ma Ding
Published: September 2011

Background

P21(WAF1/Cip1) binds to cyclin-dependent kinase complexes and inhibits their activities. It was originally described as an inhibitor of cancer cell proliferation. However, many recent studies have shown that p21 promotes tumor progression when accumulated in the cell cytoplasm. So far, little is known about the correlation between cytoplasmic p21 and drug resistance. This study was aimed to investigate the role of p21 in the cisplatin resistance of ovarian cancer.

Methods

RT-PCR, western blot and immunofluorescence were used to detect p21 expression and location in cisplatin-resistant ovarian cancer cell line C13* and its parental line OV2008. Regulation of cytoplasmic p21 was performed through transfection of p21 siRNA, Akt2 shRNA and Akt2 constitutively active vector in the two cell lines; their effects on cisplatin-induced apoptosis were evaluated by flow cytometry. Tumor tissue sections of clinical samples were analyzed by immunohistochemistry.

Results

p21 predominantly localizes to the cytoplasm in C13* compared to OV2008. Persistent exposure to low dose cisplatin in OV2008 leads to p21 translocation from nuclear to cytoplasm, while it had not impact on p21 localization in C13*. Knockdown of cytoplasmic p21 by p21 siRNA transfection in C13* notably increased cisplatin-induced apoptosis through activation of caspase 3. Inhibition of p21 translocation into the cytoplasm by transfection of Akt2 shRNA into C13* cells significantly increased cisplatin-induced apoptosis, while induction of p21 translocation into the cytoplasm by transfection of constitutively active Akt2 in OV2008 enhanced the resistance to cisplatin. Immunohistochemical analysis of clinical ovarian tumor tissues demonstrated that cytoplasmic p21 was negatively correlated with the response to cisplatin based treatment.

Conclusions

Cytoplasmic p21 is a novel biomarker of cisplatin resistance and it may represent a potential therapeutic target for ovarian tumors that are refractory to conventional treatment.
Isolation of a Highly Thermal Stable Lama Single Domain Antibody Specific for Staphylococcus aureusEnterotoxin B
Authors: Graef Russell R , Anderson George P , Doyle Katherine A , Zabetakis Dan , Sutton Felicia N , Liu Jinny L , Serrano-González Joseline , Goldman Ellen R , Cooper Lynn A
Published: September 2011

Background

Camelids and sharks possess a unique subclass of antibodies comprised of only heavy chains. The antigen binding fragments of these unique antibodies can be cloned and expressed as single domain antibodies (sdAbs). The ability of these small antigen-binding molecules to refold after heating to achieve their original structure, as well as their diminutive size, makes them attractive candidates for diagnostic assays.

Results

Here we describe the isolation of an sdAb against Staphyloccocus aureus enterotoxin B (SEB). The clone, A3, was found to have high affinity (Kd = 75 pM) and good specificity for SEB, showing no cross reactivity to related molecules such as Staphylococcal enterotoxin A (SEA), Staphylococcal enterotoxin D (SED), and Shiga toxin. Most remarkably, this anti-SEB sdAb had an extremely high Tm of 85°C and an ability to refold after heating to 95°C. The sharp Tm determined by circular dichroism, was found to contrast with the gradual decrease observed in intrinsic fluorescence. We demonstrated the utility of this sdAb as a capture and detector molecule in Luminex based assays providing limits of detection (LODs) of at least 64 pg/mL.

Conclusion

The anti-SEB sdAb A3 was found to have a high affinity and an extraordinarily high Tm and could still refold to recover activity after heat denaturation. This combination of heat resilience and strong, specific binding make this sdAb a good candidate for use in antibody-based toxin detection technologies.
The effect on survival of continuing chemotherapy to near death
Authors: Saito Akiko M , Landrum Mary Beth , Neville Bridget A , Ayanian John Z , Earle Craig C
Published: September 2011

Background

Overuse of anti-cancer therapy is an important quality-of-care issue. An aggressive approach to treatment can have negative effects on quality of life and cost, but its effect on survival is not well-defined.

Methods

Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 7,879 Medicare-enrolled patients aged 65 or older who died after having survived at least 3 months after diagnosis of advanced non-small cell lung cancer (NSCLC) between 1991 and 1999. We used Cox proportional hazards regression analysis, propensity scores, and instrumental variable analysis (IVA) to compare survival among patients who never received chemotherapy (n = 4,345), those who received standard chemotherapy but not within two weeks prior to death (n = 3,235), and those who were still receiving chemotherapy within 14 days of death (n = 299). Geographic variation in the application of chemotherapy was used as the instrument for IVA.

Results

Receipt of chemotherapy was associated with a 2-month improvement in overall survival. However, based on three different statistical approaches, no additional survival benefit was evident from continuing chemotherapy within 14 days of death. Moreover, patients receiving chemotherapy near the end of life were much less likely to enter hospice (81% versus 51% with no chemotherapy and 52% with standard chemotherapy, P < 0.001), or were more likely to be admitted within only 3 days of death.

Conclusions

Continuing chemotherapy for advanced NSCLC until very near death is associated with a decreased likelihood of receiving hospice care but not prolonged survival. Oncologists should strive to discontinue chemotherapy as death approaches and encourage patients to enroll in hospice for better end-of-life palliative care.
Effects of amodiaquine and artesunate on sulphadoxine-pyrimethamine pharmacokinetic parameters in children under five in Mali
Authors: Tekete Mamadou M , Toure Sékou , Fredericks Alfia , Beavogui Abdoul H , Sangare Cheick PO , Evans Alicia , Smith Peter , Maiga Hamma , Traore Zoumana I , Doumbo Ogobara K , Barnes Karen I , Djimde Abdoulaye A
Published: September 2011

Background

Sulphadoxine-pyrimethamine, in combination with artesunate or amodiaquine, is recommended for the treatment of uncomplicated malaria and is being evaluated for intermittent preventive treatment. Yet, limited data is available on pharmacokinetic interactions between these drugs.

Methods

In a randomized controlled trial, children aged 6-59 months with uncomplicated falciparum malaria, received either one dose of sulphadoxine-pyrimethamine alone (SP), one dose of SP plus three daily doses of amodiaquine (SP+AQ) or one dose of SP plus 3 daily doses of artesunate (SP+AS). Exactly 100 μl of capillary blood was collected onto filter paper before drug administration at day 0 and at days 1, 3, 7, 14, 21 and 28 after drug administration for analysis of sulphadoxine and pyrimethamine pharmacokinetic parameters.

Results

Fourty, 38 and 31 patients in the SP, SP+AQ and SP+AS arms, respectively were included in this study. The concentrations on day 7 (that are associated with therapeutic efficacy) were similar between the SP, SP+AQ and SP+AS treatment arms for sulphadoxine (median [IQR] 35.25 [27.38-41.70], 34.95 [28.60-40.85] and 33.40 [24.63-44.05] μg/mL) and for pyrimethamine (56.75 [46.40-92.95], 58.75 [43.60-98.60] and 59.60 [42.45-86.63] ng/mL). There were statistically significant differences between the pyrimethamine volumes of distribution (4.65 [3.93-6.40], 4.00 [3.03-5.43] and 5.60 [4.40-7.20] L/kg; p = 0.001) and thus elimination half-life (3.26 [2.74 -3.82], 2.78 [2.24-3.65] and 4.02 [3.05-4.85] days; p < 0.001). This study confirmed the lower SP concentrations previously reported for young children when compared with adult malaria patients.

Conclusion

Despite slight differences in pyrimethamine volumes of distribution and elimination half-life, these data show similar exposure to SP over the critical initial seven days of treatment and support the current use of SP in combination with either AQ or AS for uncomplicated falciparum malaria treatment in young Malian children.
The in-vitro evaluation of antibacterial, antifungal and cytotoxic properties of Marrubium vulgare L. essential oil grown in Tunisia
Authors: Zarai Zied , Kadri Adel , Ben Chobba Ines , Ben Mansour Riadh , Bekir Ahmed , Mejdoub Hafedh , Gharsallah Néji
Published: September 2011

Background

In order to validate its antiseptic and anticancer properties with respect to traditional uses, we have screened for the first time the antimicrobial activity of aerial parts of M. vulgare L. essential oil against different pathogenic microorganisms and the cytotoxic activity against HeLa cell lines.

Methods

The agar disk diffusion method was used to study the antibacterial activity of M. vulgare essential oil against 12 bacterial and 4 fungi strains. The disc diameters of zone of inhibition (DD), the minimum inhibitory concentrations (MIC) and the concentration inhibiting 50% (IC50) were investigated to characterize the antimicrobial activities of this essential oil. The in vitro cytotoxicity of M. vulgare essential oil was examined using a modified MTT assay; the viability and the IC50 were used to evaluate this test.

Results

The antimicrobial activity of the essential oil was investigated in order to evaluate its efficacy against the different tested microorganisms. The present results results showed a significant activity against microorganisms especially Gram (+) bacteria with inhibition zones and minimal inhibitory concentration values in the range of 6.6-25.2 mm and 1120-2600 μg/ml, respectively, whereas Gram (-) bacteria exhibited a higher resistance. As far as the antifungal activity, among four strains tested, Botrytis cinerea exhibited the strongest activity with inhibition zones of 12.6 mm. However, Fusarium solani, Penicillium digitatum and Aspergillus niger were less sensitive to M. vulgare essential oil. About the citotoxicity assay, this finding indicate the capability of this essential oil to inhibited the proliferation of HeLa cell lines under some conditions with IC50 value of 0.258 μg/ml.

Conclusion

This investigation showed that the M. vulgare essential oil has a potent antimicrobial activity against some Gram (+) pathogenic bacteria and Botrytis cinerea fungi. The present studies confirm the use of this essential oil as anticancer agent. Further research is required to evaluate the practical values of therapeutic applications.
Noise reduction for periodic signals using high-resolution frequency analysis
Authors: Yoshizawa Toshio , Hirobayashi Shigeki , Misawa Tadanobu
Published: September 2011

The spectrum subtraction method is one of the most common methods by which to remove noise from a spectrum. Like many noise reduction methods, the spectrum subtraction method uses discrete Fourier transform (DFT) for frequency analysis. There is generally a trade-off between frequency and time resolution in DFT. If the frequency resolution is low, then the noise spectrum can overlap with the signal source spectrum, which makes it difficult to extract the latter signal. Similarly, if the time resolution is low, rapid frequency variations cannot be detected. In order to solve this problem, as a frequency analysis method, we have applied non-harmonic analysis (NHA), which has high accuracy for detached frequency components and is only slightly affected by the frame length. Therefore, we examined the effect of the frequency resolution on noise reduction using NHA rather than DFT as the preprocessing step of the noise reduction process. The accuracy in extracting single sinusoidal waves from a noisy environment was first investigated. The accuracy of NHA was found to be higher than the theoretical upper limit of DFT. The effectiveness of NHA and DFT in extracting music from a noisy environment was then investigated. In this case, NHA was found to be superior to DFT, providing an approximately 2 dB improvement in SNR.
Complementary tensor-driven image coherence diffusion for oriented structure enhancement
Authors: Hong-mei Zhang , Ming-xi Wan , Zheng-zhong Bian
Published: September 2011

Oriented structure enhancement plays important role in computer vision tasks, where the diffusion is encouraged along the preferred direction instead of perpendicular to it. By analyzing the differential geometric property of the oriented structure, a complementary tensor is proposed by combining the first and the second-order structure tensors as complementary descriptors, which can precisely analyze not only the step edges, but also the weak edges such as narrow peak or ridge-like structures. Complementary diffusion tensor is constructed from the new structure tensor, which steers coherence diffusion for oriented structure enhancement. Furthermore, fast algorithm based on additive operator splitting scheme is used for numerical solution, which is much faster than usual approach. The experimental results on several images are provided. Experiments show that the image diffusion process steered by the new complementary tensor can strengthen the oriented structures and also close the interrupted lines as well. Both strong and weak edges are enhanced while noise is removed. Our approach is very promising and could be applied to many other images.
Optimization of adefovir therapy in chronic hepatitis B according to baseline predictors and on-treatment HBV DNA: a 5-Year prospective study
Authors: Lu Hui , Geng Da Ying , Shen Fei , Zhang Jing Yao , Lu Bing , Ma Li Xian
Published: September 2011

Background

Adefovir Dipivoxil (ADV) is an important agent to suppress hepatitis B virus (HBV) replication with suboptimal effect on virological and serological response. To optimize Adefovir therapy in chronic hepatitis B (CHB) patients with hepatitis B e antigen (HBeAg) positive, we studied the baseline parameters and on-treatment HBV DNA for favorable outcomes.

Methods

48 patients were enrolled in the study and followed up for 5 years prospectively. Baseline characteristics, virological, serological and biochemical parameters as well as on treatment HBV DNA were assessed in prediction of favorable outcomes.

Results

1. The patients with baseline alanine aminotransferase (ALT) ≥5 × the upper limit of normal (ULN, 40 IU/L) had higher rates of viral response (VR), HBeAg loss and HBeAg seroconversion at year 5 compared to the patients with ALT < 5 × ULN (VR: 75% vs 43.8%, p = 0.035; HBeAg loss: 43.9% vs 13.8%, p = 0.017; HBeAg seroconversion: 37.9% vs 13.8%, p = 0.035); Patients with baseline HBV DNA < 109copies/ml and ALT ≥3 × ULN had more chance of HBeAg seroconversion (40.9% vs 8.7%, p = 0.012), while in patients with HBeAg < 800 s/co or HBsAg < 5000 IU/ml higher rates of HBeAg loss were achieved. 2. HBV DNA level < 104copies/ml at week 24 was predictive for VR (96.0% vs 40.9%, P < 0.001), HBeAg loss (84.0% vs 36.3%, P = 0.001) and HBeAg seroconversion (36.0% vs 9.1%, P = 0.030).

Conclusions

ADV treatment should be started for patients with baseline ALT≥5 × ULN or patients with ALT≥3 × ULN and HBV DNA < 109copies/ml. Lower level of HBeAg(< 800 s/co) and HBsAg(< 5000 IU/ml) may be regarded as referenced factors. In patients with serum HBV DNA < 104copies/ml at week 24 the therapy should continue, and a favorable outcome may be achieved in 5 years or longer.
Expression of an IRF-3 fusion protein and mouse estrogen receptor, inhibits hepatitis C viral replication in RIG-I-deficient Huh 7.5 cells
Authors: Yao Luyu , Yan Xiaobo , Dong Huijia , Nelson David R , Liu Chen , Li Xiaoyu
Published: September 2011

Interferon Regulatory Factor-3 (IRF-3) plays a central role in the induction of interferon (IFN) production and succeeding interferon-stimulated genes (ISG) expression en route for restraining hepatitis C virus (HCV) infection. Here, we established a stable Huh7.5-IRF3ER cell line expressing a fusion protein of IRF-3 and mouse estrogen receptor (ER) to examine IFN production and anti-HCV effects of IRF-3 in retinoic acid inducible-gene-I (RIG-I) deficient Huh 7.5 cells. Homodimerization of the IRF-3ER fusion protein was detected by Western blotting after treatment with the estrogen receptor agonist 4-hydrotamoxifen (4-HT) in Huh7.5-IRF3ER cells. Expression of IFN-α, IFN-β, and their inhibitory effects on HCV replication were demonstrated by real-time polymerase chain reaction (PCR). Peak expression of IFN-α and IFN-β was achieved 24-hours post 4-HT treatment, coinciding with the appearance of phosphorylated signal transducer and activator of transcription (STAT) proteins. Additionally, HCV viral replication declined in time-dependent fashion. In previous studies, a novel IFN-mediated pathway regulating expression of 1-8U and heterogeneous nuclear ribonucleoprotein M (hnRNP M) inhibited HCV internal ribosomal entry site (IRES)-dependent translation. When expression of ISGs such as 1-8U and hnRNP M were measured in 4-HT-treated Huh7.5-IRF3ER cells, both genes were positively regulated by activation of the IRF-3ER fusion protein. In conclusion, the anti-HCV effects of IRF-3ER homodimerization inhibited HCV RNA replication as well as HCV IRES-dependent translation in Huh7.5-IRF3ER cells. The results of this study indicate that IRF-3ER homodimerization is a key step to restore IFN expression in Huh7.5-IRF3ER cells and in achieving its anti-HCV effects.
Targeting Adenosine Monophosphate-Activated Protein Kinase (AMPK) in Preclinical Models Reveals a Potential Mechanism for the Treatment of Neuropathic Pain
Authors: Melemedjian Ohannes K , Asiedu Marina N , Tillu Dipti V , Sanoja Raul , Yan Jin , Lark Arianna , Khoutorsky Arkady , Johnson Jessica , Peebles Katherine A , Lepow Talya , Sonenberg Nahum , Dussor Gregory , Price Theodore J
Published: September 2011

Neuropathic pain is a debilitating clinical condition with few efficacious treatments, warranting development of novel therapeutics. We hypothesized that dysregulated translation regulation pathways may underlie neuropathic pain. Peripheral nerve injury induced reorganization of translation machinery in the peripheral nervous system of rats and mice, including enhanced mTOR and ERK activity, increased phosphorylation of mTOR and ERK downstream targets, augmented eIF4F complex formation and enhanced nascent protein synthesis. The AMP activated protein kinase (AMPK) activators, metformin and A769662, inhibited translation regulation signaling pathways, eIF4F complex formation, nascent protein synthesis in injured nerves and sodium channel-dependent excitability of sensory neurons resulting in a resolution of neuropathic allodynia. Therefore, injury-induced dysregulation of translation control underlies pathology leading to neuropathic pain and reveals AMPK as a novel therapeutic target for the potential treatment of neuropathic pain.
Migraine Attacks the Basal Ganglia
Authors: Maleki Nasim , Becerra Lino , Nutile Lauren , Pendse Gautam , Brawn Jennifer , Bigal Marcelo , Burstein Rami , Borsook David
Published: September 2011

Background:

With time, episodes of migraine headache afflict patients with increased frequency, longer duration and more intense pain. While episodic migraine may be defined as 1-14 attacks per month, there are no clear-cut phases defined, and those patients with low frequency may progress to high frequency episodic migraine and the latter may progress into chronic daily headache (> 15 attacks per month). The pathophysiology of this progression is completely unknown. Attempting to unravel this phenomenon, we used high field (human) brain imaging to compare functional responses, functional connectivity and brain morphology in patients whose migraine episodes did not progress (LF) to a matched (gender, age, age of onset and type of medication) group of patients whose migraine episodes progressed (HF).

Results:

In comparison to LF patients, responses to pain in HF patients were significantly lower in the caudate, putamen and pallidum. Paradoxically, associated with these lower responses in HF patients, gray matter volume of the right and left caudate nuclei were significantly larger than in the LF patients. Functional connectivity analysis revealed additional differences between the two groups in regard to response to pain.

Conclusions:

Supported by current understanding of basal ganglia role in pain processing, the findings suggest a significant role of the basal ganglia in the pathophysiology of the episodic migraine.
The Brazilian Network for HIV‐1 Genotyping External Quality Control Assurance Programme
Authors: Souza Denise CF , Sucupira Maria Cecilia A , Brindeiro Rodrigo M , Fernandez José Carlos C , Sabino Ester C , Inocencio Lilian A , Diaz Ricardo S
Published: September 2011

The Brazilian network for genotyping is composed of 21 laboratories that perform and analyze genotyping tests for all HIV‐infected patients within the public system, performing approximately 25,000 tests per year. We assessed the interlaboratory and intralaboratory reproducibility of genotyping systems by creating and implementing a local external quality control evaluation. Plasma samples from HIV‐1‐infected individuals (with low and intermediate viral loads) or RNA viral constructs with specific mutations were used. This evaluation included analyses of sensitivity and specificity of the tests based on qualitative and quantitative criteria, which scored laboratory performance on a 100‐point system. Five evaluations were performed from 2003 to 2008, with 64% of laboratories scoring over 80 points in 2003, 81% doing so in 2005, 56% in 2006, 91% in 2007, and 90% in 2008 (Kruskal‐Wallis, p = 0.003). Increased performance was aided by retraining laboratories that had specific deficiencies. The results emphasize the importance of investing in laboratory training and interpretation of DNA sequencing results, especially in developing countries where public (or scarce) resources are used to manage the AIDS epidemic.
Red blood cell transfusion and outcomes in patients with acute lung injury, sepsis and shock
Authors: Parsons Elizabeth C , Hough Catherine L , Seymour Christopher W , Cooke Colin R , Rubenfeld Gordon D , Watkins Timothy R ,   the NHLBI ARDS Network
Published: September 2011

Introduction

In this study, we sought to determine the association between red blood cell (RBC) transfusion and outcomes in patients with acute lung injury (ALI), sepsis and shock.

Methods

We performed a secondary analysis of new-onset ALI patients enrolled in the Acute Respiratory Distress Syndrome Network Fluid and Catheter Treatment Trial (2000 to 2005) who had a documented ALI risk factor of sepsis or pneumonia and met shock criteria (mean arterial pressure (MAP) < 60 mmHg or vasopressor use) within 24 hours of randomization. Using multivariable logistic regression, we examined the association between RBC transfusion and 28-day mortality after adjustment for age, sex, race, randomization arm and Acute Physiology and Chronic Health Evaluation III score. Secondary end points included 90-day mortality and ventilator-free days (VFDs). Finally, we examined these end points among the subset of subjects meeting prespecified transfusion criteria defined by five simultaneous indicators: hemoglobin < 10.2 g/dL, central or mixed venous oxygen saturation < 70%, central venous pressure ≥ 8 mmHg, MAP ≥ 65 mmHg, and vasopressor use.

Results

We identified 285 subjects with ALI, sepsis, shock and transfusion data. Of these, 85 also met the above prespecified transfusion criteria. Fifty-three (19%) of the two hundred eighty-five subjects with shock and twenty (24%) of the subset meeting the transfusion criteria received RBC transfusion within twenty-four hours of randomization. We found no independent association between RBC transfusion and 28-day mortality (odds ratio = 1.49, 95% CI (95% confidence interval) = 0.77 to 2.90; P = 0.23) or VFDs (mean difference = -0.35, 95% CI = -4.03 to 3.32; P = 0.85). Likewise, 90-day mortality and VFDs did not differ by transfusion status. Among the subset of patients meeting the transfusion criteria, we found no independent association between transfusion and mortality or VFDs.

Conclusions

In patients with new-onset ALI, sepsis and shock, we found no independent association between RBC transfusion and mortality or VFDs. The physiological criteria did not identify patients more likely to be transfused or to benefit from transfusion.
Effects of changes in arterial pressure on organ perfusion during septic shock
Authors: Thooft Aurélie , Favory Raphaël , Salgado Diamantino Ribeiro , Taccone Fabio S , Donadello Katia , De Backer Daniel , Creteur Jacques , Vincent Jean-Louis
Published: September 2011

Introduction

Septic shock is characterized by altered tissue perfusion associated with persistent arterial hypotension. Vasopressor therapy is generally required to restore organ perfusion but the optimal mean arterial pressure (MAP) that should be targeted is uncertain. The aim of this study was to assess the effects of increasing MAP using norepinephrine (NE) on hemodynamic and metabolic variables and on microvascular reactivity in patients with septic shock.

Methods

This was a single center, prospective, interventional study conducted in the medico-surgical intensive care unit of a university hospital. Thirteen patients in septic shock for less than 48 hours who required NE administration were included. NE doses were adjusted to obtain MAPs of 65, 75, 85 and (back to) 65 mmHg. In addition to hemodynamic and metabolic variables, we measured thenar muscle oxygen saturation (StO2), using near infrared spectroscopy (NIRS), with serial vaso-occlusive tests (VOTs) on the upper arm. We also evaluated the sublingual microcirculation using sidestream dark field (SDF) imaging in 6 of the patients.

Results

Increasing NE dose was associated with an increase in cardiac output (from 6.1 to 6.7 l/min, P<0.05) and mixed venous oxygen saturation (SvO2, from 70.6 to 75.9%, P<0.05). Oxygen consumption (VO2) remained stable, but blood lactate levels decreased. There was a significant increase in the ascending slope of StO2 (from 111 to 177%/min, P<0.05) after VOTs. SDF imaging showed an increase in perfused vessel density (PVD, from 11.0 to 13.2 n/mm, P<0.05) and in microvascular flow index (MFI, from 2.4 to 2.9, P<0.05).

Conclusions

In this series of patients with septic shock, increasing MAP above 65 mmHg with NE was associated with increased cardiac output, improved microvascular function, and decreased blood lactate concentrations. The microvascular response varied among patients suggesting that individualization of blood pressure targets may be warranted.
Investigation of the differential potentials of TLR agonists to elicit uveitis in mice
Authors: Allensworth Jordan J , Planck Stephen R , Rosenbaum James T , Rosenzweig Holly L
Published: September 2011

TLRs are critical for host defense and innate immunity. Emerging evidence also supports a role for TLRs in many chronic inflammatory diseases, including inflammatory eye disease, known as uveitis. The activation of TLR4 by endotoxin induces a standard model of murine uveitis. How activation of additional TLRs influences the onset and/or severity of anterior uveitis has not been examined. We sought to elucidate the potential of TLRs (TLR1/2, TLR2/6, TLR3, TLR4, TLR5, TLR7/8, and TLR9) to trigger uveitis in mice. Directly stimulated iris/ciliary body explants demonstrated a marked increase in production of inflammatory cytokines TNF-α, IL-6, IP-10/CXCL10, MCP-1, and KC with relatively little production of IFN-γ, IL-10, IL-12p40, IL-12p70, IL-17, IL-1β, IL-4, or RANTES. The cytokine-response profiles were comparable amongst the TLR agonists, albeit some differences were noted, such as greater IP-10 production following TLR3 activation. Intra-ocular injection of TLR agonists increased leukocyte interactions with the endothelium of the iris vasculature and resulted in chemotaxis into the iris tissue. Assessment of leukocytic responses by ivt videomicroscopy and histology revealed quantitative differences amongst responses to the TLR agonists with respect to the timing and numbers of rolling, adhering, iris-infiltrating, and aqueous humor-infiltrating cells, along with cytokine levels in vivo. Our data demonstrate the eye's responsiveness to a diverse array of microbial products, which activates TLRs, and reveal differences in relative cellular response among the various TLR agonists in vivo.
Myeloid-derived suppressor cells help protective immunity toLeishmania majorinfection despite suppressed T cell responses
Authors: Pereira Wânia F , Ribeiro-Gomes Flávia L , Guillermo Landi V Costilla , Vellozo Natália S , Montalvão Fabrício , DosReis George A , Lopes Marcela F
Published: September 2011

Th1/Th2 cytokines play a key role in immune responses to Leishmania major by controlling macrophage activation for NO production and parasite killing. MDSCs, including myeloid precursors and immature monocytes, produce NO and suppress T cell responses in tumor immunity. We hypothesized that NO-producing MDSCs could help immunity to L. major infection. Gr1hi(Ly6Chi) CD11bhi MDSCs elicited by L. major infection suppressed polyclonal and antigen-specific T cell proliferation. Moreover, L. major-induced MDSCs killed intracellular parasites in a NO-dependent manner and reduced parasite burden in vivo. By contrast, treatment with ATRA, which induces MDSCs to differentiate into macrophages, increased development of lesions, parasite load, and T cell proliferation in draining LNs. Altogether, these results indicate that NO-producing MDSCs help protective immunity to L. major infection, despite suppressed T cell proliferation.
Involvement of Progranulin in Hypothalamic Glucose Sensing and Feeding Regulation
Authors: Kim Hyun-Kyong , Shin Mi-Seon , Youn Byung-Soo , Namkoong Churl , Gil So Young , Kang Gil Myoung , Yu Ji Hee , Kim Min-Seon
Published: September 2011

Progranulin (PGRN) is a secreted glycoprotein with multiple biological functions, including modulation of wound healing and inflammation. Hypothalamic PGRN has been implicated in the development of sexual dimorphism. In the present study, a potential role for PGRN in the hypothalamic regulation of appetite and body weight was investigated. In adult rodents, PGRN was highly expressed in periventricular tanycytes and in hypothalamic neurons, which are known to contain glucose-sensing machinery. Hypothalamic PGRN expression levels were decreased under low-energy conditions (starvation and 2-deoxy-D-glucose administration) but increased under high-energy condition (postprandially). Intracerebrovetricular administration of PGRN significantly suppressed nocturnal feeding as well as hyperphagia induced by 2-deoxyglucose, neuropeptide Y, and Agouti-related peptide. Moreover, the inhibition of hypothalamic PGRN expression or action increased food intake and promoted weight gain, suggesting that endogenous PGRN functions as an appetite suppressor in the hypothalamus. Investigation of the mechanism of action revealed that PGRN diminished orexigenic neuropeptide Y and Agouti-related peptide production but stimulated anorexigenic proopiomelanocortin production, at least in part through the regulation of hypothalamic AMP-activated protein kinase. Notably, PGRN was also expressed in hypothalamic microglia. In diet-induced obese mice, microglial PGRN expression was increased, and the anorectic response to PGRN was blunted. These findings highlight a physiological role for PGRN in hypothalamic glucose-sensing and appetite regulation. Alterations in hypothalamic PGRN production or action may be linked to appetite dysregulation in obesity.
Effects of Acute Changes in Neonatal Leptin Levels on Food Intake and Long-Term Metabolic Profiles in Rats
Authors: Granado Miriam , García-Cáceres Cristina , Fuente-Martín Esther , Díaz Francisca , Mela Virginia , Viveros Maria-Paz , Argente Jesús , Chowen Julie A.
Published: September 2011

In rodents there is a rise in serum leptin levels between postnatal days (PND) 5 and 14, with this neonatal leptin surge reported to modulate the maturation of hypothalamic circuits involved in appetite regulation. We hypothesized that acute changes in neonatal leptin levels have different long-term metabolic effects depending on how and when this surge is modified. To advance the timing of the normal leptin peak, male Wistar rats were injected with leptin (sc, 3 μg/g) on PND 2. To ablate the leptin peak on PND 10, a pegylated leptin antagonist (sc, 9 μg/g) was injected. Controls received vehicle. All rats were allowed to eat ad libitum until PND 150. Increased leptin on PND 2 reduced food intake (P < 0.01) after 3 months of age with no effect on body weight. Levels of total ghrelin were reduced (P < 0.001) and acylated ghrelin increased (P < 0.05), with no other modifications in metabolic hormones. In contrast, treatment with the leptin antagonist on PND 9 did not affect food intake but reduced body weight beginning around PND 60 (P < 0.02). This was associated with a reduction in fat mass, insulin (P < 0.01), and leptin (P < 0.007) levels and an increase in testosterone levels (P < 0.01). Hypothalamic neuropeptide Y (P < 0.05) and leptin receptor (P < 0.005) mRNA levels were reduced, whereas mRNA levels for uncoupling protein 2 (P < 0.005) were increased in visceral fat, which may indicate an increase in energy expenditure. In conclusion, acute changes in neonatal leptin levels induce different metabolic profiles depending on how and when leptin levels are modified.
MIG-15 and ERM-1 promote growth cone directional migration in parallel to UNC-116 and WVE-1
Authors: Teulière Jérôme , Gally Christelle , Garriga Gian , Labouesse Michel , Georges-Labouesse Elisabeth
Published: September 2011

Neurons require precise targeting of their axons to form a connected network and a functional nervous system. Although many guidance receptors have been identified, much less is known about how these receptors signal to direct growth cone migration. We used Caenorhabditis elegans motoneurons to study growth cone directional migration in response to a repellent UNC-6 (netrin homolog) guidance cue. The evolutionarily conserved kinase MIG-15 [homolog of Nck-interacting kinase (NIK)] regulates motoneuron UNC-6-dependent repulsion through unknown mechanisms. Using genetics and live imaging techniques, we show that motoneuron commissural axon morphology defects in mig-15 mutants result from impaired growth cone motility and subsequent failure to migrate across longitudinal obstacles or retract extra processes. To identify new genes acting with mig-15, we screened for genetic enhancers of the mig-15 commissural phenotype and identified the ezrin/radixin/moesin ortholog ERM-1, the kinesin-1 motor UNC-116 and the actin regulator WVE-1 complex. Genetic analysis indicates that mig-15 and erm-1 act in the same genetic pathway to regulate growth cone migration and that this pathway functions in parallel to the UNC-116/WVE-1 pathway. Further, time-lapse imaging of growth cones in mutants suggests that UNC-116 might be required to stimulate protrusive activity at the leading edge, whereas MIG-15 and ERM-1 maintain low activity at the rear edge. Together, these results support a model in which the MIG-15 kinase and the UNC-116–WVE-1 complex act on opposite sides of the growth cone to promote robust directional migration.