bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of artemether-lumefantrine as a treatment for uncomplicated Plasmodium vivax malaria in eastern Sudan
Authors: Abdallah Tajeldin M , Ali Abdel Aziem A , Bakri Mohammed , Gasim Gasim I , Musa Imad R , Adam Ishag
Published: December 2012

Background

Artemisinin-based combination therapy (ACT) is the treatment of choice for uncomplicated Plasmodium falciparum malaria in most areas of the world, where malaria is endemic, including Sudan. However, few published data are available on the use of ACT for treatment of P. vivax malaria.

Methods

This study was conducted at a health centre in Kassala, eastern Sudan, from October to December 2011. Patients with uncomplicated P. vivax malaria received artemether-lumefantrine (AL) tablets (containing 20mg artemether and 120 mg lumefantrine) and were monitored for 28 days.

Results

Out of the 43 cases enrolled in this study, 38 completed the 28-day follow-up. Their mean age was 25.1 years (SD: 1.5). On day 3 following AL treatment, all of the patients were afebrile and aparasitaemic. By day 28, all 38 patients exhibited adequate clinical and parasitological responses to AL treatment. The cure rate was 100% and 88.4% for the per protocol analysis andfor the intention to treat analysis, respectively. Mild adverse effects (nausea, vomiting, abdominal pain, dizziness and/or rash) that resolved spontaneously were observed in four (10.5%) of the patients.

Conclusion

AL combination therapy was fully effective for treatment of P. vivax malaria in the study in eastern Sudan.

Trial registration

Trial. Gov: NCT01625871
Inhibitory effect of the combination therapy of simvastatin and pinocembrin on atherosclerosis in apoE-deficient mice
Authors: Sang Hui , Yuan Na , Yao Shutong , Li Furong , Wang Jiafu , Fang Yongqi , Qin Shucun
Published: December 2012

The present study was performed to investigate the effects of the combination therapy of pinocembrin and simvastatin on the atherosclerotic lesions development in the ApoE−/− mice.

Methods

Eight-week-old male ApoE−/− mice were fed high fat diet (HFD) and treated with simvastatin (10 mg/kg per day), pinocembrin (20 mg/kg per day), or the combination therapy (simvastatin 5 mg/kg per day and pinocembrin 20 mg/kg per day) for 14 weeks. The serum lipid levels, nitric oxide (NO), endothelin (ET), superoxide dismutase (SOD) and malondialdehyde (MDA) were determined with spectrophotometric measurement and ELISA assay. Vascular endothelial growth factor (VEGF) in serum and aortic root was detected. En face analyses of atherosclerotic lesion in whole aorta and aortic root sections were performed with plaque staining using oil red O.

Results

The combination treatment with simvastatin and pinocembrin resulted in significantly decreased levels of serum total cholesterol, triglycerides and low-density lipoprotein cholesterol, augmented NO levels and SOD activity, inhibited ET and VEGF expression. Immunohistochemistry of aortic valve sections revealed that the combination therapy also suppressed the expression of VEGF induced by HFD. In addition, HFD-induced arterial wall lipid disposition displayed by oil red O staining was reduced significantly in aortic root and whole aorta en face in the combination administrated mice. The effect of the combination was superior to simvastatin alone.

Conclusion

The combination of simvastatin and pinocembrin synergistically inhibited atherosclerotic lesion development in ApoE−/− mice with hyperlipidemia, which is partially dependent on the protective of vascular endothelium.
Minimally invasive liver resection to obtain tumor-infiltrating lymphocytes for adoptive cell therapy in patients with metastatic melanoma
Authors: Alvarez-Downing Melissa M , Inchauste Suzanne M , Dudley Mark E , White Donald E , Wunderlich John R , Rosenberg Steven A , Kammula Udai S
Published: December 2012

Background

Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma has been reported to have a 56% overall response rate with 20% complete responders. To increase the availability of this promising therapy in patients with advanced melanoma, a minimally invasive approach to procure tumor for TIL generation is warranted.

Methods

A feasibility study was performed to determine the safety and efficacy of laparoscopic liver resection to generate TIL for ACT. Retrospective review of a prospectively maintained database identified 22 patients with advanced melanoma and visceral metastasis (AJCC Stage M1c) who underwent laparoscopic liver resection between 1 October 2005 and 31 July 2011. The indication for resection in all patients was to receive postoperative ACT with TIL.

Results

Twenty patients (91%) underwent resection utilizing a closed laparoscopic technique, one required hand-assistance and another required conversion to open resection. Median intraoperative blood loss was 100 mL with most cases performed without a Pringle maneuver. Median hospital stay was 3 days. Three (14%) patients experienced a complication from resection with no mortality. TIL were generated from 18 of 22 (82%) patients. Twelve of 15 (80%) TIL tested were found to have in vitro tumor reactivity. Eleven patients (50%) received the intended ACT. Two patients were rendered no evidence of disease after surgical resection, with one undergoing delayed ACT with generated TIL after relapse. Objective tumor response was seen in 5 of 11 patients (45%) who received TIL, with one patient experiencing an ongoing complete response (32+ months).

Conclusions

Laparoscopic liver resection can be performed with minimal morbidity and serve as an effective means to procure tumor to generate therapeutic TIL for ACT to patients with metastatic melanoma.
A generalization of Geraghty's theorem in partially ordered metric spaces and applications to ordinary differential equations
Authors: Gordji Madjid Eshaghi , Ramezani Maryam , Cho Yeol Je , Pirbavafa Saeideh
Published: December 2012

The purpose of this article is to present some fixed point theorems for generalized contraction in partially ordered complete metric spaces. As an application, we give an existence and uniqueness for the solution of an initial-boundary-value problem.

2000 Mathematics Subject Classification: 47H10; 54H25; 34B15.
Efficacy of single dose of gentamicin in combination with metronidazole versus multiple doses for prevention of post-caesarean infection: study protocol for a randomized controlled trial
Authors: Lyimo Fadhili M , Massinde Anthony N , Kidenya Benson R , Konje Evelyne , Mshana Stephen E
Published: December 2012

Background

Caesarean section is a commonly performed operation worldwide. It has been found to increase rates of maternal infectious morbidities more than five times when compared to vaginal delivery. Provision of intravenous prophylactic antibiotics 30 to 60 minutes prior to caesarean section has been found to reduce post-caesarean infection tremendously. Many centers recommend provision of a single dose of antibiotics, as repeated doses offer no benefit over a single dose.

At Bugando Medical Centre post caesarean infection is among the top five causes of admission at the post-natal ward. Unfortunately, there is no consistent protocol for the administration of antibiotic prophylaxis to patients who are designated for caesarean section. Common practice and generally the clinician’s preference are to provide repeated dosages of antibiotic prophylaxis after caesarean section to most of the patients. This study aims to determine the comparative efficacy of a single dose of gentamicin in combination with metronidazole versus multiple doses for prevention of post caesarean infection.

Methods/Design

The study is an interventional, open-label, two-armed, randomized, single-center study conducted at Bugando Medical Centre Mwanza, Tanzania. It is an ongoing trial for the period of seven months; 490 eligible candidates will be enrolled in the study. Study subjects will be randomly allocated into two study arms; “A” and “B”. Candidates in “A” will receive a single dose of gentamicin in combination with metronidazole 30 to 60 minutes prior to the operation and candidates in “B” will receive the same drugs prior to the operation and continue with gentamicin and metronidazole for 24 hours. The two groups will be followed up for a period of one month and assessed for signs and symptoms of surgical site infection.

Data will be extracted from a case record form and entered into Epi data3.1 software before being transferred to SPSS version 17.0 for analysis. The absolute difference in proportion of women who develop surgical site infection in the two study arms will be the effectiveness of one regime over the other.

Trial registration

Current Controlled TrialsISRCTN44462542.
Use of dermal-fat grafts in the post-oncological reconstructive surgery of atrophies in the zygomatic region: clinical evaluations in the patients undergone to previous radiation therapy
Authors: Inchingolo Francesco , Tatullo Marco , Pacifici Andrea , Gargari Marco , Inchingolo Alessio D , Inchingolo Angelo M , Dipalma Gianna , Marrelli Massimo , Abenavoli Fabio M , Pacifici Luciano
Published: December 2012

Introduction

Grafting of autologous adipose tissue can be recommended in some cases of facial plastic surgery. Rhabdomyosarcoma is a type of cancer that can also affect the orbit. Enucleation of the eye can cause atrophy of the corresponding hemiface and decreased orbital growth.

Case report

We report a case of a female patient with a medical history of surgical enucleation of the right eyeball, who had received rhabdomyosarcoma radiation therapy in her youth. The patient presented with a depression in the right zygomatic region. We took a dermal-fat flap from the abdominal region, which had been previously treated.

Results

The surgical outcome, 48 hours, and much clearly 31 days after the surgery, revealed that the right zygomatic region had returned to its proper anatomical shape, although there were still signs of postoperative edema.

Discussion

Very damaged tissues, like those exposed to radiation therapy, are generally not suitable for grafting of adipose tissue.

Conclusions

In the described case, we achieved a technically and aesthetically satisfying result despite the patient's medical history involving several perplexities about the use of autologous dermal-fat tissues, because of prior radiation therapy exposure. The clinical case shows that even a region exposed to radiation therapy can be a valid receiving bed for dermal-fat grafting.
The technical feasibility of an image-guided intensity-modulated radiotherapy (IG-IMRT) to perform a hypofractionated schedule in terms of toxicity and local control for patients with locally advanced or recurrent pancreatic cancer
Authors: Son Seok Hyun , Song Jin Ho , Choi Byung Ock , Kang Young nam , Lee Myung Ah , Kang Ki Mun , Jang Hong Seok
Published: December 2012

Background

The purpose of this study was to evaluate the technical feasibility of an image-guided intensity modulated radiotherapy (IG-IMRT) using involved-field technique to perform a hypofractionated schedule for patients with locally advanced or recurrent pancreatic cancer.

Methods

From May 2009 to November 2011, 12 patients with locally advanced or locally recurrent pancreatic cancer received hypofractionated CCRT using TomoTherapy Hi-Art with concurrent and sequential chemotherapy at Seoul St. Mary’s Hospital, the Catholic University of Korea. The total dose delivered was 45 Gy in 15 fractions or 50 Gy in 20 fractions. The target volume did not include the uninvolved regional lymph nodes. Treatment planning and delivery were performed using the IG-IMRT technique. The follow-up duration was a median of 31.1 months (range: 5.7-36.3 months).

Results

Grade 2 or worse acute toxicities developed in 7 patients (58%). Grade 3 or worse gastrointestinal and hematologic toxicity occurred in 0% and 17% of patients, respectively. In the response evaluation, the rates of partial response and stable disease were 58% and 42%, respectively. The rate of local failure was 8% and no regional failure was observed. Distant failure was the main cause of treatment failure. The progression-free survival and overall survival durations were 7.6 and 12.1 months, respectively.

Conclusion

The involved-field technique and IG-IMRT delivered via a hypofractionated schedule are feasible for patients with locally advanced or recurrent pancreatic cancer.
On optimal control policy for probabilistic Boolean network: a state reduction approach
Authors: Chen Xi , Jiang Hao , Qiu Yushan , Ching Wai-Ki
Published: December 2012

Background

Probabilistic Boolean Network (PBN) is a popular model for studying genetic regulatory networks. An important and practical problem is to find the optimal control policy for a PBN so as to avoid the network from entering into undesirable states. A number of research works have been done by using dynamic programming-based (DP) method. However, due to the high computational complexity of PBNs, DP method is computationally inefficient for a large size network. Therefore it is natural to seek for approximation methods.

Results

Inspired by the state reduction strategies, we consider using dynamic programming in conjunction with state reduction approach to reduce the computational cost of the DP method. Numerical examples are given to demonstrate both the effectiveness and the efficiency of our proposed method.

Conclusions

Finding the optimal control policy for PBNs is meaningful. The proposed problem has been shown to be∑2p - hard. By taking state reduction approach into consideration, the proposed method can speed up the computational time in applying dynamic programming-based algorithm. In particular, the proposed method is effective for larger size networks.
Elsholtzia: phytochemistry and biological activities
Authors: Guo Zhiqin , Liu Zizhen , Wang Xiaohong , Liu Weirui , Jiang Rui , Cheng Ruiyang , She Gaimei
Published: December 2012

Plants of the genus Elsholtzia (Lamiaceae) have a long history of medicinal use in folk. The phytochemical investigations revealed the presence of flavonoids, phenylpropanoids, terpenoids, and other compounds. Abundant volatile components are also identified. Pure compounds, volatile constituents and crude extracts from the genus exhibited a wide spectrum of in vitro and in vivo pharmacological activities. The aims of this review hopefully provide comprehensive information on the distribution, phytochemistry, volatile components, and pharmacological research of Elsholtzia for exploring the potential and advance researches.
Growth promotion and colonization of switchgrass (Panicum virgatum) cv. Alamo by bacterial endophyte Burkholderia phytofirmans strain PsJN
Authors: Kim Seonhwa , Lowman Scott , Hou Guichuan , Nowak Jerzy , Flinn Barry , Mei Chuansheng
Published: December 2012

Background

Switchgrass is one of the most promising bioenergy crop candidates for the US. It gives relatively high biomass yield and can grow on marginal lands. However, its yields vary from year to year and from location to location. Thus it is imperative to develop a low input and sustainable switchgrass feedstock production system. One of the most feasible ways to increase biomass yields is to harness benefits of microbial endophytes.

Results

We demonstrate that one of the most studied plant growth promoting bacterial endophytes,Burkholderia phytofirmansstrain PsJN, is able to colonize and significantly promote growth of switchgrass cv. Alamo underin vitro, growth chamber, and greenhouse conditions. In severalin vitroexperiments, the average fresh weight of PsJN-inoculated plants was approximately 50% higher than non-inoculated plants. When one-month-old seedlings were grown in a growth chamber for 30 days, the PsJN-inoculated Alamo plants had significantly higher shoot and root biomass compared to controls. Biomass yield (dry weight) averaged from five experiments was 54.1% higher in the inoculated treatment compared to non-inoculated control. Similar results were obtained in greenhouse experiments with transplants grown in 4-gallon pots for two months. The inoculated plants exhibited more early tillers and persistent growth vigor with 48.6% higher biomass than controls. We also found that PsJN could significantly promote growth of switchgrass cv. Alamo under sub-optimal conditions. However, PsJN-mediated growth promotion in switchgrass is genotype specific.

Conclusions

Our results showB. phytofirmansstrain PsJN significantly promotes growth of switchgrass cv. Alamo under different conditions, especially in the early growth stages leading to enhanced production of tillers. This phenomenon may benefit switchgrass establishment in the first year. Moreover, PsJN significantly stimulated growth of switchgrass cv. Alamo under sub-optimal conditions, indicating that the use of the beneficial bacterial endophytes may boost switchgrass growth on marginal lands and significantly contribute to the development of a low input and sustainable feedstock production system.
Fibrosis in systemic sclerosis: common and unique pathobiology
Authors: Bhattacharyya Swati , Wei Jun , Tourtellotte Warren G , Hinchcliff Monique , Gottardi Cara G , Varga John
Published: December 2012

Fibrosis in systemic sclerosis (SSc), a complex polygenic disease associated with autoimmunity and proliferative/obliterative vasculopathy, shares pathobiologic features in common with other fibrosing illnesses, but also has distinguishing characteristics. Fibroblast activation induced by transforming growth factor-β (TGF-β), Wnts and innate immune receptors, along with oxidative stress and reactive oxygen species (ROS) are implicated in pathogenesis. On the other hand, the roles of endothelial-mesenchymal differentiation and bone marrow-derived fibrocytes remain to be established. Fibrotic responses are modulated by transcriptional activators and cofactors, epigenetic factors, and microRNAs that can amplify or inhibit ligand-induced signaling. The nuclear orphan receptor PPAR-γ appears to be important in governing the duration and intensity of fibroblast activation and mesenchymal progenitor cell differentiation, and defects in PPAR-γ expression or function in SSc may underlie the uncontrolled progression of fibrosis. Identifying the perturbations in signaling pathways and cellular differentiation programs responsible for tissue damage and fibrosis in SSc allows their selective targeting using novel compounds, or by innovative uses of already-approved drugs (drug repurposing).
Thematic clustering of text documents using an EM-based approach
Authors: Kim Sun , Wilbur W John
Published: December 2012

Clustering textual contents is an important step in mining useful information on the web or other text-based resources. The common task in text clustering is to handle text in a multi-dimensional space, and to partition documents into groups, where each group contains documents that are similar to each other. However, this strategy lacks a comprehensive view for humans in general since it cannot explain the main subject of each cluster. Utilizing semantic information can solve this problem, but it needs a well-defined ontology or pre-labeled gold standard set. In this paper, we present a thematic clustering algorithm for text documents. Given text, subject terms are extracted and used for clustering documents in a probabilistic framework. An EM approach is used to ensure documents are assigned to correct subjects, hence it converges to a locally optimal solution. The proposed method is distinctive because its results are sufficiently explanatory for human understanding as well as efficient for clustering performance. The experimental results show that the proposed method provides a competitive performance compared to other state-of-the-art approaches. We also show that the extracted themes from the MEDLINE® dataset represent the subjects of clusters reasonably well.
The global epidemiology of clonorchiasis and its relation with cholangiocarcinoma
Authors: Qian Men-Bao , Chen Ying-Dan , Liang Song , Yang Guo-Jing , Zhou Xiao-Nong
Published: December 2012

This paper reviews the epidemiological status and characteristics of clonorchiasis at global level and the etiological relationship betweenClonorchis sinensisinfection and cholangiocarcinoma (CCA). A conservative estimation was made that 15 million people were infected in the world in 2004, of which over 85% distributed in China. The epidemiology of clonorchiasis is characterized by rising trend in its prevalence, variability among sexes and age, as well as endemicity in different regions. More data indicate thatC. sinensisinfection is carcinogenic to human, and it is predicted that nearly 5 000 CCA cases attributed toC. sinensisinfection may occur annually in the world decades later, with its overall odds ratio of 4.47. Clonorchiasis is becoming one major public health problem in east Asia, and it is worthwhile to carry out further epidemiological studies.
Fluid management in critically ill patients: the role of extravascular lung water, abdominal hypertension, capillary leak, and fluid balance
Authors: Cordemans Colin , De laet Inneke , Van Regenmortel Niels , Schoonheydt Karen , Dits Hilde , Huber Wolfgang , Malbrain Manu LNG
Published: December 2012

Introduction

Capillary leak in critically ill patients leads to interstitial edema. Fluid overload is independently associated with poor prognosis. Bedside measurement of intra-abdominal pressure (IAP), extravascular lung water index (EVLWI), fluid balance, and capillary leak index (CLI) may provide a valuable prognostic tool in mechanically ventilated patients.

Methods

We performed an observational study of 123 mechanically ventilated patients with extended hemodynamic monitoring, analyzing process-of-care variables for the first week of ICU admission. The primary outcome parameter was 28-day mortality. ΔmaxEVLWI indicated the maximum difference between EVLWI measurements during ICU stay. Patients with a ΔmaxEVLWI <−2 mL/kg were called 'responders'. CLI was defined as C-reactive protein (milligrams per deciliter) over albumin (grams per liter) ratio and conservative late fluid management (CLFM) as even-to-negative fluid balance on at least two consecutive days.

Results

CLI had a biphasic course. ΔmaxEVLWI was lower if CLFM was achieved and in survivors (−2.4 ± 4.8 vs 1.0 ± 5.5 mL/kg, p = 0.001; −3.3 ± 3.8 vs 2.5 ± 5.3 mL/kg, p = 0.001, respectively). No CLFM achievement was associated with increased CLI and IAPmean on day 3 and higher risk to be nonresponder (odds ratio (OR) 2.76, p = 0.046; OR 1.28, p = 0.011; OR 5.52, p = 0.001, respectively). Responders had more ventilator-free days during the first week (2.5 ± 2.3 vs 1.5 ± 2.3, p = 0.023). Not achieving CLFM and being nonresponder were strong independent predictors of mortality (OR 9.34, p = 0.001 and OR 7.14, p = 0.001, respectively).

Conclusion

There seems to be an important correlation between CLI, EVLWI kinetics, IAP, and fluid balance in mechanically ventilated patients, associated with organ dysfunction and poor prognosis. In this context, we introduce the global increased permeability syndrome.
Intra-abdominal pressure and abdominal perfusion pressure in cirrhotic patients with septic shock
Authors: Al-Dorzi Hasan M , Tamim Hani M , Rishu Asgar H , Aljumah Abdulrahman , Arabi Yaseen M
Published: December 2012

Background

The importance of intra-abdominal pressure (IAP) and abdominal perfusion pressure (APP) in cirrhotic patients with septic shock is not well studied. We evaluated the relationship between IAP and APP and outcomes of cirrhotic septic patients, and assessed the ability of these measures compared to other common resuscitative endpoints to differentiate survivors from nonsurvivors.

Methods

This study was a post hoc analysis of a randomized double-blind placebo-controlled trial in which mean arterial pressure (MAP), central venous oxygen saturation (ScvO2) and IAP were measured every 6 h in 61 cirrhotic septic patients admitted to the intensive care unit. APP was calculated as MAP - IAP. Intra-abdominal hypertension (IAH) was defined as mean IAP ≥ 12 mmHg, and abdominal hypoperfusion as mean APP < 60 mmHg. Measured outcomes included ICU and hospital mortality, need for renal replacement therapy (RRT) and ventilator- and vasopressor-free days.

Results

IAH prevalence on the first ICU day was 82%, and incidence in the first 7 days was 97%. Compared to patients with normal IAP, IAH patients had significantly higher ICU mortality (74.0% vs. 27.3%, p = 0.005), required more RRT (78.0% vs. 45.5%, p = 0.06) and had lower ventilator- and vasopressor-free days. On a multivariate logistic regression analysis, IAH was an independent predictor of both ICU mortality (odds ratio (OR), 12.20; 95% confidence interval (CI), 1.92 to 77.31, p = 0.008) and need for RRT (OR, 6.78; 95% CI, 1.29 to 35.70, p = 0.02). Using receiver operating characteristic curves, IAP (area under the curve (AUC) = 0.74, p = 0.004), APP (AUC = 0.71, p = 0.01), Acute Physiology and Chronic Health Evaluation II score (AUC = 0.71, p = 0.02), but not MAP, differentiated survivors from nonsurvivors.

Conclusions

IAH is highly prevalent in cirrhotic patients with septic shock and is associated with increased ICU morbidity and mortality.
On the Exponential Ergodicity of Lévy-Driven Ornstein–Uhlenbeck Processes
Authors: Wang Jian
Published: December 2012

Based on the explicit coupling property, the ergodicity and the exponential ergodicity of Lévy-driven Ornstein–Uhlenbeck processes are established.
On a new Class of Tempered Stable Distributions: Moments and Regular Variation
Authors: Grabchak Michael
Published: December 2012

We extend the class of tempered stable distributions, which were first introduced in Rosiński (2007). Our new class allows for more structure and more variety of the tail behaviors. We discuss various subclasses and the relations between them. To characterize the possible tails, we give detailed results about finiteness of various moments. We also give necessary and sufficient conditions for the tails to be regularly varying. This last part allows us to characterize the domain of attraction to which a particular tempered stable distribution belongs.
Maximizing the Size of the Giant
Authors: Britton Tom , Trapman Pieter
Published: December 2012

Consider a random graph where the mean degree is given and fixed. In this paper we derive the maximal size of the largest connected component in the graph. We also study the related question of the largest possible outbreak size of an epidemic occurring ‘on’ the random graph (the graph describing the social structure in the community). More precisely, we look at two different classes of random graphs. First, the Poissonian random graph in which each node i is given an independent and identically distributed (i.i.d.) random weight Xi with E(Xi)=µ, and where there is an edge between i and j with probability 1-e-XiXj/(µ n), independently of other edges. The second model is the thinned configuration model in which the n vertices of the ground graph have i.i.d. ground degrees, distributed as D, with E(D) = µ. The graph of interest is obtained by deleting edges independently with probability 1-p. In both models the fraction of vertices in the largest connected component converges in probability to a constant 1-q, where q depends on X or D and p. We investigate for which distributions X and D with given µ and p, 1-q is maximized. We show that in the class of Poissonian random graphs, X should have all its mass at 0 and one other real, which can be explicitly determined. For the thinned configuration model, D should have all its mass at 0 and two subsequent positive integers.
How much energy should manipulative parasites leave to their hosts to ensure altered behaviours?
Authors: Maure Fanny , Brodeur Jacques , Hughes David , Thomas Frédéric
Published: December 2012

Although host manipulation is likely to be costly for parasites, we still have a poor understanding of the energetic aspects underlying this strategy. It is traditionally assumed that physiological costs are inevitably associated with mechanisms evolved by parasites to induce the required changes in host behaviours. While most energetic expenditures of parasites relate primarily to bringing about the altered behaviours, manipulative parasites also have to consider the condition of their host during the manipulation. Here, we suggest that because of this trade-off, the energy required to accomplish parasite-induced behaviours may represent a key energetic constraint for parasites. Depending on the energetic expenditures specific to each type of manipulation, parasites should undergo selection to secure resources for their host to allow them to perform manipulated behaviours.
Morphologic and Clinicopathologic Features of Lung Squamous Cell Carcinomas ExpressingSox2
Authors: Brcic Luka , Sherer Carol K. , Shuai Yongli , Hornick Jason L. , Chirieac Lucian R. , Dacic Sanja
Published: December 2012

Sox2 amplification was recently reported as a common event in squamous cell carcinomas (SCCs) occurring at different anatomic sites including the lung. The objective of the study was to determine morphologic and clinicopathologic characteristics of lung SCCs with respect to Sox2 protein expression and gene amplification. One hundred forty-seven surgically treated non–small cell lung carcinomas were analyzed for Sox2 gene amplification by using fluorescence in situ hybridization and protein expression using immunohistochemical analysis. SCC showed more frequent Sox2 protein expression (52/66; 79%) than adenocarcinomas (ADC) (14/76; 18%) (P < .0001). Similarly, Sox2 amplification was more frequent in SCCs (52/70; 72%) than in ADCs (6/77; 8%) (P < .0001). Sox2 protein expression was associated with better overall survival in SCC (66 vs 14 months; P =.048). SCC with basaloid differentiation and severe nuclear atypia exhibited more intense Sox2 protein expression than other tumors. Sox2 appears to be an important gene in lung squamous cell carcinogenesis that in particular drives the development of poorly differentiated tumors.
ERG Protein Expression in Human Tumors Detected With a Rabbit Monoclonal Antibody
Authors: Yaskiv Oksana , Rubin Brian P. , He Huiying , Falzarano Sara , Magi-Galluzzi Cristina , Zhou Ming
Published: December 2012

Avian v-ets erythroblastosis virus E26 oncogene homolog (ERG) is highly sensitive and specific for endothelial neoplasms and specific for prostate carcinoma. We characterized a rabbit anti-ERG antibody as an immunohistochemical agent to detect ERG expression in various tumors using tissue microarrays with a wide array of epithelial and mesenchymal tumors. ERG was positive in 63 (38%) of 168 prostate carcinomas and negative in all other epithelial tumors. ERG was positive in all 125 vascular lesions. It was also positive in the sarcomatoid component of a high-grade urothelial carcinoma and 6 (40%) of 15 meningiomas. Twelve (80%) of 15 meningiomas were positive for Fli1, including all 6 ERG-positive cases. Positive immunostaining with this antibody is therefore highly specific for prostate carcinoma and vascular lesions, with a few caveats. ERG is rarely detected in nonvascular mesenchymal tumors with this antibody. Furthermore, about 40% of meningiomas are also positive for ERG immunohistochemically, probably because of cross-reactivity with Fli1.
Interobserver Agreement Among Pathologists for Semiquantitative Hormone Receptor Scoring in Breast Carcinoma
Authors: Cohen David A. , Dabbs David J. , Cooper Kristine L. , Amin Milon , Jones Terrell E. , Jones Mirka W. , Chivukula Mamatha , Trucco Giuliana A. , Bhargava Rohit
Published: December 2012

The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines recommend reporting of hormone receptor test results in a semiquantitative manner. This study used 74 resected estrogen receptor (ER)–positive invasive breast cancers to determine reproducibility of semiquantitative scoring of hormone receptors using the H-score method. Four pathologists independently scored each slide. Agreement among observers was analyzed via Fleiss κ statistics on ER and progesterone receptor (PR) categorical scores. Intraclass correlation coefficient (ICC) was used to estimate the interobserver agreement for ER and PR H-scores on a continuous scale (0–300). There was 100% agreement for categorical ER results (κ = 1) and 97% agreement (κ = 0.823, P < .001) for categorical PR results. For quantitative H-scores, ICC agreement was 0.85 (95% confidence interval [CI] = 0.79–0.90) for ER and 0.87 (95% CI = 0.82–0.92) for PR. Because the H-score provides a continuous measure of tumor hormone receptor content, we suggest universal adoption of this method.
Simultaneous Analysis of HER2 Gene and Protein on a Single Slide Facilitates HER2 Testing of Breast and Gastric Carcinomas
Authors: Hirschmann Astrid , Lamb Tiffany Ann , Marchal Georges , Padilla Mary , Diebold Joachim
Published: December 2012

This study sought to evaluate a new combined gene and protein detection platform in the context of HER2 evaluation in breast and gastric carcinomas. HER2 immunohistochemistry (IHC) and dual color in situ hybridization (Dual ISH) were combined on a single slide. Results were compared with conventional HER2 IHC and fluorescence ISH. Results from the gene and protein assay were reliable and highly reproducible for both breast and gastric carcinomas. Concordance was found between conventional HER2 IHC and ISH testing and the gene and protein assay in the same laboratory (>95% for Dual ISH; lower for IHC because of different antibody clones), between IHC and Dual ISH performed on the same slide (>92%), and in the gene and protein assays between laboratories (>96%). This cost- and time-effective method provides fast and definitive results (IHC confirmed by means of Dual ISH) to aid in rapid treatment decisions. It can also be applied to other gene and protein combinations.
Varenicline: Implications for the Field
Authors: Bobak Alex
Published: December 2012

Varenicline tartrate (Champix) is the first in a new class of therapy for smoking cessation and has been available on NHS prescription since December 2006. It has received approval from The National Institute for Health and Clinical Excellence (NICE) and the Scottish Medicines Consortium and NICE final guidance was issued in July 2007. Varenicline is a partial agonist of the nicotinic receptor (·4, 2 subtype) and also prevents nicotine from binding to it. Studies comparing safety and efficacy with bupropion (Zyban) have been favourable and efficacy with varenicline has been shown to be greater than that with bupropion. A study comparing the nicotine patch is due for publication this year. Varenicline has a good safety profile with nausea being the most common side effect in about a third of those who take it. Despite the treatment's advantages there have been numerous issues which have affected its use. These include funding and administrative issues and this paper looks at ways of overcoming those barriers to prescribing what is a valuable addition to the range of treatments on offer to smokes who want to stop.
Nerve Growth Factor-Induced Formation of Axonal Filopodia and Collateral Branches Involves the Intra-Axonal Synthesis of Regulators of the Actin-Nucleating Arp2/3 Complex
Authors: Spillane Mirela , Ketschek Andrea , Donnelly Chris J. , Pacheco Almudena , Twiss Jeffrey L. , Gallo Gianluca
Published: December 2012

Nerve growth factor (NGF) induces collateral branching along sensory axons by promoting the formation of axonal filopodia dependent on the actin-nucleating Arp2/3 complex. This study shows that chicken embryonic sensory axons contain mRNAs for the actin-nucleating Arp2/3 complex activator WAVE1 and the complex stabilizer cortactin. NGF increases the axonal levels of WAVE1 and cortactin through localized protein synthesis even in axons isolated from the cell body. Inhibition of protein synthesis in severed axons impairs NGF-induced branching, the formation of axonal filopodia, and the initiation of Arp2/3-dependent axonal actin patches, which serve as precursors to the emergence of filopodia. Overexpression of WAVE1 or cortactin in axons not treated with NGF increased the rate of actin patch formation and the frequency of the emergence of filopodia from actin patches, respectively. Antisense inhibition of cortactin mRNA translation in isolated axons blocked NGF-induced filopodia. NGF also activated the Rac1 GTPase, which drives WAVE1 activity, in a protein synthesis-independent manner. Similarly, inhibition of protein synthesis did not impair the effects of NGF on the axonal microtubule cytoskeleton during branching. The effects of NGF on Rac1 activity and increases in axonal levels of WAVE1 and cortactin were both dependent on phosphoinositide 3-kinase (PI3K) signaling. Collectively, the data indicate that NGF promotes sensory axon branching through regulation of the actin cytoskeleton using both canonical signaling mechanisms and intra-axonal protein synthesis downstream of PI3K signaling. Finally, we present experimental evidence of axonal mRNA translation in sensory axons in the living embryonic spinal cord.
Brain-Derived Neurotrophic Factor-Dependent Synaptic Plasticity Is Suppressed by Interleukin-1β via p38 Mitogen-Activated Protein Kinase
Authors: Tong Liqi , Prieto G. Aleph , Kramár Enikö A. , Smith Erica D. , Cribbs David H. , Lynch Gary , Cotman Carl W.
Published: December 2012

Evolving evidence suggests that brain inflammation and the buildup of proinflammatory cytokine increases the risk for cognitive decline and cognitive dysfunction. Interleukin-1β (IL-1β), acting via poorly understood mechanisms, appears to be a key cytokine in causing these deleterious effects along with a presumably related loss of long-term potentiation (LTP)-type synaptic plasticity. We hypothesized that IL-1β disrupts brain-derived neurotrophic factor (BDNF) signaling cascades and thereby impairs the formation of filamentous actin (F-actin) in dendritic spines, an event that is essential for the stabilization of LTP. Actin polymerization in spines requires phosphorylation of the filament severing protein cofilin and is modulated by expression of the immediate early gene product Arc. Using rat organotypic hippocampal cultures, we found that IL-1β suppressed BDNF-dependent regulation of Arc and phosphorylation of cofilin and cAMP response element-binding protein (CREB), a transcription factor regulating Arc expression. IL-1β appears to act on BDNF signal transduction by impairing the phosphorylation of insulin receptor substrate 1, a protein that couples activation of the BDNF receptor TrkB to downstream signaling pathways regulating CREB, Arc, and cofilin. IL-1β upregulated p38 mitogen-activated protein kinase (MAPK), and inhibiting p38 MAPK prevented IL-1β from disrupting BDNF signaling. IL-1β also prevented the formation of F-actin in spines and impaired the consolidation, but not the induction, of BDNF-dependent LTP in acute hippocampal slices. The suppressive effect of IL-1β on F-actin and LTP was prevented by inhibiting p38 MAPK. These findings define a new mechanism for the action of IL-1β on LTP and point to a potential therapeutic target to restore synaptic plasticity.
Increasing CRTC1 Function in the Dentate Gyrus during Memory Formation or Reactivation Increases Memory Strength without Compromising Memory Quality
Authors: Sekeres Melanie J. , Mercaldo Valentina , Richards Blake , Sargin Derya , Mahadevan Vivek , Woodin Melanie A. , Frankland Paul W. , Josselyn Sheena A.
Published: December 2012

Memory stabilization following encoding (synaptic consolidation) or memory reactivation (reconsolidation) requires gene expression and protein synthesis (Dudai and Eisenberg, 2004; Tronson and Taylor, 2007; Nader and Einarsson, 2010; Alberini, 2011). Although consolidation and reconsolidation may be mediated by distinct molecular mechanisms (Lee et al., 2004), disrupting the function of the transcription factor CREB impairs both processes (Kida et al., 2002; Mamiya et al., 2009). Phosphorylation of CREB at Ser133 recruits CREB binding protein (CBP)/p300 coactivators to activate transcription (Chrivia et al., 1993; Parker et al., 1996). In addition to this well known mechanism, CREB regulated transcription coactivators (CRTCs), previously called transducers of regulated CREB (TORC) activity, stimulate CREB-mediated transcription, even in the absence of CREB phosphorylation. Recently, CRTC1 has been shown to undergo activity-dependent trafficking from synapses and dendrites to the nucleus in excitatory hippocampal neurons (Ch'ng et al., 2012). Despite being a powerful and specific coactivator of CREB, the role of CRTC in memory is virtually unexplored. To examine the effects of increasing CRTC levels, we used viral vectors to locally and acutely increase CRTC1 in the dorsal hippocampus dentate gyrus region of mice before training or memory reactivation in context fear conditioning. Overexpressing CRTC1 enhanced both memory consolidation and reconsolidation; CRTC1-mediated memory facilitation was context specific (did not generalize to nontrained context) and long lasting (observed after virally expressed CRTC1 dissipated). CREB overexpression produced strikingly similar effects. Therefore, increasing CRTC1 or CREB function is sufficient to enhance the strength of new, as well as established reactivated, memories without compromising memory quality.
G9a Histone Methyltransferase Activity in Retinal Progenitors Is Essential for Proper Differentiation and Survival of Mouse Retinal Cells
Authors: Katoh Kimiko , Yamazaki Ryoji , Onishi Akishi , Sanuki Rikako , Furukawa Takahisa
Published: December 2012

In vertebrate retinal development, various transcription factors are known to execute essential activities in gene regulation. Although epigenetic modification is considered to play a pivotal role in retinal development, the exactin vivorole of epigenetic regulation is still poorly understood. We observed that G9a histone methyltransferase, which methylates histone H3 at lysine 9 (H3K9), is substantially expressed in the mouse retina throughout development. To addressin vivoG9a function in the mouse retina, we ablatedG9ain retinal progenitor cells by conditional gene knock-out (G9a Dkk3CKO). TheG9a Dkk3CKO retina exhibited severe morphological defects, including photoreceptor rosette formation, a partial loss of the outer nuclear layer, elevated cell death, and persistent cell proliferation. Progenitor cell-related genes, including several cyclins, Hes1, Chx10, and Lhx2, are methylated on histone H3K9 in the wild-type retina, but they were defective in H3K9 methylation and improperly upregulated at late developmental stages in theG9a Dkk3CKO retina. Notably, conditional depletion ofG9ain postmitotic photoreceptor precursors (G9a CrxCKO) led to the development of an almost normal retina, indicating that G9a activity mainly in retinal progenitor cells, but not in photoreceptor precursors, is essential for normal terminal differentiation of and survival of the retina. Our results suggest that proper epigenetic marks in progenitor cells are important for subsequent appropriate terminal differentiation and survival of retinal cells by repressing progenitor cell-related genes in differentiating retinal cells.
Deficits in Morphofunctional Maturation of Hippocampal Mossy Fiber Synapses in a Mouse Model of Intellectual Disability
Authors: Lanore Frederic , Labrousse Virginie F. , Szabo Zsolt , Normand Elisabeth , Blanchet Christophe , Mulle Christophe
Published: December 2012

Thegrik2gene, coding for the kainate receptor subunit GluK2 (formerly GluR6), is associated with autism spectrum disorders and intellectual disability. Here, we tested the hypothesis that GluK2 could play a role in the appropriate maturation of synaptic circuits involved in learning and memory. We show that both the functional and morphological maturation of hippocampal mossy fiber to CA3 pyramidal cell (mf-CA3) synapses is delayed in mice deficient for the GluK2 subunit (GluK2−/−). In GluK2−/−mice this deficit is manifested by a transient reduction in the amplitude of AMPA-EPSCs at a critical time point of postnatal development, whereas the NMDA component is spared. By combining multiple probability peak fluctuation analysis and immunohistochemistry, we have provided evidence that the decreased amplitude reflects a decrease in the quantal size per mf-CA3 synapse and in the number of active synaptic sites. Furthermore, we analyzed the time course of structural maturation of CA3 synapses by confocal imaging of YFP-expressing cells followed by tridimensional (3D) anatomical reconstruction of thorny excrescences and presynaptic boutons. We show that major changes in synaptic structures occur subsequently to the sharp increase in synaptic transmission, and more importantly that the course of structural maturation of synaptic elements is impaired in GluK2−/−mice. This study highlights how a mutation in a gene linked to intellectual disability in the human may lead to a transient reduction of synaptic strength during postnatal development, impacting on the proper formation of neural circuits linked to memory.
How Silent Is Silent Reading? Intracerebral Evidence for Top-Down Activation of Temporal Voice Areas during Reading
Authors: Perrone-Bertolotti Marcela , Kujala Jan , Vidal Juan R. , Hamame Carlos M. , Ossandon Tomas , Bertrand Olivier , Minotti Lorella , Kahane Philippe , Jerbi Karim , Lachaux Jean-Philippe
Published: December 2012

As you might experience it while reading this sentence, silent reading often involves an imagery speech component: we can hear our own “inner voice” pronouncing words mentally. Recent functional magnetic resonance imaging studies have associated that component with increased metabolic activity in the auditory cortex, including voice-selective areas. It remains to be determined, however, whether this activation arises automatically from early bottom-up visual inputs or whether it depends on late top-down control processes modulated by task demands. To answer this question, we collaborated with four epileptic human patients recorded with intracranial electrodes in the auditory cortex for therapeutic purposes, and measured high-frequency (50–150 Hz) “gamma” activity as a proxy of population level spiking activity. Temporal voice-selective areas (TVAs) were identified with an auditory localizer task and monitored as participants viewed words flashed on screen. We compared neural responses depending on whether words were attended or ignored and found a significant increase of neural activity in response to words, strongly enhanced by attention. In one of the patients, we could record that response at 800 ms in TVAs, but also at 700 ms in the primary auditory cortex and at 300 ms in the ventral occipital temporal cortex. Furthermore, single-trial analysis revealed a considerable jitter between activation peaks in visual and auditory cortices. Altogether, our results demonstrate that the multimodal mental experience of reading is in fact a heterogeneous complex of asynchronous neural responses, and that auditory and visual modalities often process distinct temporal frames of our environment at the same time.