bluuebunny/crossref_metadata_2025 huggingface dataset:
Prime immunization with rotavirus VLP 2/6 followed by boosting with an adenovirus expressing VP6 induces protective immunization against rotavirus in mice
Authors: Zhou Hongli , Guo Li , Wang Min , Qu Jianguo , Zhao Zhendong , Wang Jianwei , Hung Tao
Published: January 2011

Background

Rotavirus (RV) is the main cause of severe gastroenteritis in children. An effective vaccination regime against RV can substantially reduce morbidity and mortality. Previous studies have demonstrated the efficacy of virus-like particles formed by RV VP2 and VP6 (VLP2/6), as well as that of recombinant adenovirus expressing RV VP6 (rAd), in eliciting protective immunities against RV. However, the efficacy of such prime-boost strategy, which incorporates VLP and rAd in inducing protective immunities against RV, has not been addressed. We assessed the immune effects of different regimens in mice, including rAd prime-VLP2/6 boost (rAd+VLP), VLP2/6 prime-rAd boost (VLP+rAd), rAd alone, and VLP alone.

Results

Mice immunized with the VLP+rAd regimen elicit stronger humoral, mucosal, and cellular immune responses than those immunized with other regimens. RV challenging experiments showed that the highest reduction (92.9%) in viral shedding was achieved in the VLP+rAd group when compared with rAd+VLP (25%), VLP alone (75%), or rAd alone (40%) treatment groups. The reduction in RV shedding in mice correlated with fecal IgG (r = 0.95773, P = 0.04227) and IgA (r = 0.96137, P = 0.038663).

Conclusions

A VLP2/6 prime-rAd boost regimen is effective in conferring immunoprotection against RV challenge in mice. This finding may lay the groundwork for an alternative strategy in novel RV vaccine development.
Blocking Spinal CCR2 with AZ889 Reversed Hyperalgesia in a Model of Neuropathic Pain
Authors: Serrano Alexandre , Paré Michel , McIntosh Fraser , Elmes Steven JR , Martino Giovanni , Jomphe Claudia , Lessard Etienne , Lembo Paola MC , Vaillancourt François , Perkins Martin N , Cao Chang Qing
Published: January 2011

Background:

The CCR2/CCL2 system has been identified as a regulator in the pathogenesis of neuropathy-induced pain. However, CCR2 target validation in analgesia and the mechanism underlying antinociception produced by CCR2 antagonists remains poorly understood. In this study, in vitro and in vivo pharmacological approaches using a novel CCR2 antagonist, AZ889, strengthened the hypothesis of a CCR2 contribution to neuropathic pain and provided confidence over the possibilities to treat neuropathic pain with CCR2 antagonists.

Results:

We provided evidence that dorsal root ganglia (DRG) cells harvested from CCI animals responded to stimulation by CCL2 with a concentration-dependent calcium rise involving PLC-dependent internal stores. This response was associated with an increase in evoked neuronal action potentials suggesting these cells were sensitive to CCR2 signalling. Importantly, treatment with AZ889 abolished CCL2-evoked excitation confirming that this activity is CCR2-mediated. Neuronal and non-neuronal cells in the spinal cord were also excited by CCL2 applications indicating an important role of spinal CCR2 in neuropathic pain. We next showed that in vivo spinal intrathecal injection of AZ889 produced dose-dependent analgesia in CCI rats. Additionally, application of AZ889 to the exposed spinal cord inhibited evoked neuronal activity and confirmed that CCR2-mediated analgesia involved predominantly the spinal cord. Furthermore, AZ889 abolished NMDA-dependent wind-up of spinal withdrawal reflex pathway in neuropathic animals giving insight into the spinal mechanism underlying the analgesic properties of AZ889.

Conclusions:

Overall, this study strengthens the important role of CCR2 in neuropathic pain and highlights feasibility that interfering on this mechanism at the spinal level with a selective antagonist can provide new analgesia opportunities.
Dietary Grape Seed Polyphenols Repress Neuron and Glia Activation in Trigeminal Ganglion and Trigeminal Nucleus Caudalis
Authors: Cady Ryan J , Hirst Jeffery J , Durham Paul L
Published: January 2011

Background:

Inflammation and pain associated with temporomandibular joint disorder, a chronic disease that affects 15% of the adult population, involves activation of trigeminal ganglion nerves and development of peripheral and central sensitization. Natural products represent an underutilized resource in the pursuit of safe and effective ways to treat chronic inflammatory diseases. The goal of this study was to investigate effects of grape seed extract on neurons and glia in trigeminal ganglia and trigeminal nucleus caudalis in response to persistent temporomandibular joint inflammation. Sprague Dawley rats were pretreated with 200 mg/kg/d MegaNatural-BP grape seed extract for 14 days prior to bilateral injections of complete Freund's adjuvant into the temporomandibular joint capsule.

Results:

In response to grape seed extract, basal expression of mitogen-activated protein kinase phosphatase 1 was elevated in neurons and glia in trigeminal ganglia and trigeminal nucleus caudalis, and expression of the glutamate aspartate transporter was increased in spinal glia. Rats on a normal diet injected with adjuvant exhibited greater basal levels of phosphorylated-p38 in trigeminal ganglia neurons and spinal neurons and microglia. Similarly, immunoreactive levels of OX-42 in microglia and glial fibrillary acidic protein in astrocytes were greatly increased in response to adjuvant. However, adjuvant-stimulated levels of phosphorylated-p38, OX-42, and glial fibrillary acidic protein were significantly repressed in extract treated animals. Furthermore, grape seed extract suppressed basal expression of the neuropeptide calcitonin gene-related peptide in spinal neurons.

Conclusions:

Results from our study provide evidence that grape seed extract may be beneficial as a natural therapeutic option for temporomandibular joint disorders by suppressing development of peripheral and central sensitization.
Analgesic Effect of Highly Reversible ω-Conotoxin FVIA on N Type Ca2+ Channels
Authors: Lee Seungkyu , Kim Yoonji , Back Seung Keun , Choi Hee-Woo , Lee Ju Yeon , Jung Hyun Ho , Ryu Jae Ha , Suh Hong-Won , Na Heung Sik , Kim Hyun Jeong , Rhim Hyewhon , Kim Jae Il
Published: January 2011

Background:

N-type Ca2+ channels (Cav2.2) play an important role in the transmission of pain signals to the central nervous system. ω-Conotoxin (CTx)-MVIIA, also called ziconotide (Prialt®), effectively alleviates pain, without causing addiction, by blocking the pores of these channels. Unfortunately, CTx-MVIIA has a narrow therapeutic window and produces serious side effects due to the poor reversibility of its binding to the channel. It would thus be desirable to identify new analgesic blockers with binding characteristics that lead to fewer adverse side effects.

Results:

Here we identify a new CTx, FVIA, from the Korean Conus Fulmen and describe its effects on pain responses and blood pressure. The inhibitory effect of CTx-FVIA on N-type Ca2+ channel currents was dose-dependent and similar to that of CTx-MVIIA. However, the two conopeptides exhibited markedly different degrees of reversibility after block. CTx-FVIA effectively and dose-dependently reduced nociceptive behavior in the formalin test and in neuropathic pain models, and reduced mechanical and thermal allodynia in the tail nerve injury rat model. CTx-FVIA (10 ng) also showed significant analgesic effects on writhing in mouse neurotransmitter- and cytokine-induced pain models, though it had no effect on acute thermal pain and interferon-γ induced pain. Interestingly, although both CTx-FVIA and CTx-MVIIA depressed arterial blood pressure immediately after administration, pressure recovered faster and to a greater degree after CTx-FVIA administration.

Conclusions:

The analgesic potency of CTx-FVIA and its greater reversibility could represent advantages over CTx-MVIIA for the treatment of refractory pain and contribute to the design of an analgesic with high potency and low side effects.
Reinforcing effects of methamphetamine in an animal model of Attention-Deficit/Hyperactivity Disorder-the Spontaneously Hypertensive Rat
Authors: dela Peña Ike , Ahn Hyung Seok , Choi Ji Young , Shin Chan Young , Ryu Jong Hoon , Cheong Jae Hoon
Published: January 2011

Substrains of the Spontaneously Hypertensive rat (SHR), a putative animal model of Attention-Deficit/Hyperactivity Disorder (ADHD), have demonstrated increased sensitivity to many drugs of abuse, including psychostimulants. Therefore, it was suggested that studies in SHR may help elucidate ADHD and comorbidity with substance use disorder (SUD). However, the drug intake profile of the SHR in the most relevant animal model of drug addiction, the self-administration (SA) test, and its response on the conditioned place preference (CPP) paradigm are not yet determined. In the present study, we employed SA and CPP tests to investigate the reinforcing effects of the psychostimulant methamphetamine in an SHR substrain obtained from Charles River, Japan (SHR/NCrlCrlj). Concurrent tests were also performed in Wistar rats, the strain representing "normal" heterogeneous population. To address if the presence of ADHD behaviors further increases sensitivity to the rewarding effect of methamphetamine during adolescence, a critical period for the onset of drug abuse, CPP tests were especially conducted in adolescent Wistar and SHR/NCrlCrlj. We found that the SHR/NCrlCrlj also acquired methamphetamine SA and CPP, indicating reinforcing effects of methamphetamine in this ADHD animal model. However, we did not observe increased responsiveness of the SHR/NCrlCrlj to methamphetamine in both SA and CPP assays. This indicates that the reinforcing effects of methamphetamine may be similar in strains and that the SHR/NCrlCrlj may not adequately model ADHD and increased sensitivity to methamphetamine.
The prevention of contrast induced nephropathy by sarpogrelate in patients with chronic kidney disease: a study protocol for a prospective randomized controlled clinical trial
Authors: Park Kyungil , Chung Woo-Young , Seo Jae-Bin , Kim Sang-Hyun , Zo Joo-Hee , Kim Myung-A , Park Young-Bae
Published: January 2011

Background

Contrast-induced nephropathy (CIN) is a serious clinical problem associated with increased morbidity and mortality, particularly in patients with chronic renal insufficiency. Although some agents including hydration with saline are being prescribed to prevent renal deterioration in these high risk patients, their efficacy is not clearly defined and debatable. Therefore additional prophylactic pretreatments are needed.

Methods/Design

The present study aims to investigate differences in occurrence of CIN after sarpogrelate premedication in patients with chronic kidney disease (CKD). 268 participants, aged 20-85 years with a clinical diagnosis of CKD will be recruited. They will be randomly allocated to one of two conditions: (i) routine treatment without sarpogrelate, and (ii) routine treatment with sarpogrelate (a fixed-flexible dose of 300 mg/day). The primary outcome is the occurrence of CIN during 4 weeks after receiving contrast agent.

Discussion

As of May 2010, there were no registered trials evaluating the therapeutic potentials of sarpogrelate in preventing for CIN. If sarpogrelate decreases the worsening of renal function and occurrence of CIN, it will provide a safe, easy and inexpensive treatment option.

Trial registration

NCT01165567
A Polypill for primary prevention of cardiovascular disease: A feasibility study of the World Health Organization
Authors: Soliman Elsayed Z , Mendis Shanthi , Dissanayake Wasantha P , Somasundaram Noel P , Gunaratne Padma S , Jayasingne I Kumudini , Furberg Curt D
Published: January 2011

Background

The feasibility of conducting a large-scale Polypill clinical trial in developing countries remains unclear. More information is needed regarding the efficacy in reducing the risk factors of cardiovascular disease (CVD), side effects, improvement in adherence and physician/patient "acceptability" of the Polypill.

Methods

We conducted an open-label, parallel-group, randomized clinical trial involving three sites in Sri Lanka that enrolled a total of 216 patients without established CVD. The trial compared a Polypill (75 mg aspirin, 20 mg simvastatin, 10 mg lisinopril and 12.5 mg hydrochlorothiazide) to Standard Practice. After randomization, patients were followed monthly for three months. Pre-specified primary outcomes included reduction in systolic blood pressure, total cholesterol and estimated 10-year CVD risk. We also evaluated the recruitment process and acceptability of the Polypill by both physicians and patients.

Results

Patients were recruited in a six-month period as planned. Two hundred three patients (94.0%) completed the treatment program and returned for their three-month follow-up visits. No safety concerns were reported. These findings suggest a high rate of patient acceptability, a finding that is bolstered by the majority of patients completing the trial (90%) indicating that they would take the Polypill "for life" if proven to be effective in reducing CVD risk. Approximately 86% of the physicians surveyed agreed with and supported use of the Polypill for primary prevention and 93% for secondary prevention of CVD. Both the Polypill and Standard Practice resulted in marked reductions in systolic blood pressure, total cholesterol and 10-year risk of CVD. However, the differences between the treatment groups were not statistically significant.

Conclusions

We successfully completed a Polypill feasibility trial in Sri Lanka. We were able to document high acceptability of the Polypill to patients and physicians. We were unable to estimate the risk factor reductions on the Polypill because the control group received similar treatment with individual drugs. The Polypill was however simpler and achieved comparable risk factor reductions, highlighting its potential usefulness in the prevention of CVD.

Trial registration number

Clinicaltrials.gov: NCT00567307
Plant identification credibility in ethnobotany: a closer look at Polish ethnographic studies
Authors: Łuczaj Łukasz J
Published: January 2011

Background

This paper is an attempt to estimate the percentage of erroneously identified taxa in ethnographic studies concerning the use of plants and to propose a code for recording credibility of identification in historical ethnobotany publications.

Methods

A sample of Polish-language ethnobotanical literature (45 published sources from 1874-2005) and four collections of voucher specimens (from 1894-1975) were analyzed. Errors were detected in the publications by comparing the data with existing knowledge on the distribution of plant names and species ranges. The voucher specimens were re-examined.

A one-letter code was invented for quick identification of the credibility of data published in lists of species compiled from historical or ethnographic sources, according to the source of identification: voucher specimen, Latin binominal, botanical expert, obvious widespread name, folk name, mode of use, range, physical description or photograph. To test the use of the code an up-to-date list of wild food plants used in Poland was made.

Results

A significant difference between the ratio of mistakes in the voucher specimen collections and the ratio of detectable mistakes in the studies without herbarium documentation was found. At least 2.3% of taxa in the publications were identified erroneously (mean rate was 6.2% per publication), and in half of these mistakes even the genus was not correct. As many as 10.0% of voucher specimens (on average 9.2% per collection) were originally erroneously identified, but three quarters of the identification mistakes remained within-genus.

The species of the genera Thymus, Rumex and Rubus were most often confused within the genus.

Not all of the invented credibility codes were used in the list of wild food plants, but they may be useful for other researchers. The most often used codes were the ones signifying identification by: voucher specimen, botanical expert and by a common name used throughout the country.

Conclusions

The results of this study support the rigorous use of voucher specimens in ethnobotany, although they also reveal a relatively high percentage of misidentified taxa in the specimens studied.

The invented credibility coding system may become a useful tool for communication between historical ethnobotanists, particularly in creating larger databases.
Monitoring spindle orientation: Spindle position checkpoint in charge
Authors: Caydasi Ayse K , Ibrahim Bashar , Pereira Gislene
Published: January 2011

Every cell division in budding yeast is inherently asymmetric and counts on the correct positioning of the mitotic spindle along the mother-daughter polarity axis for faithful chromosome segregation. A surveillance mechanism named the spindle position checkpoint (SPOC), monitors the orientation of the mitotic spindle and prevents cells from exiting mitosis when the spindle fails to align along the mother-daughter axis. SPOC is essential for maintenance of ploidy in budding yeast and similar mechanisms might exist in higher eukaryotes to ensure faithful asymmetric cell division. Here, we review the current model of SPOC activation and highlight the importance of protein localization and phosphorylation for SPOC function.
A single centre experience with sequential and concomitant chemoradiotherapy in locally advanced stage IV tonsillar cancer
Authors: D Prestwich Robin J , Kancherla Kiran , Oksuz Didem Colpan , Williamson Deborah , Dyker Karen E , Coyle Catherine , Sen Mehmet
Published: January 2011

Background

Chemo-radiotherapy offers an alternative to primary surgery and adjuvant therapy for the management of locally advanced stage IV squamous cell carcinomas of the tonsil.

Methods

A retrospective analysis was performed of the outcomes of 41 patients with locoregionally advanced squamous cell carcinoma of the tonsil treated non-surgically at the Yorkshire Cancer Centre between January 2004 and December 2005. Due to long radiotherapy waiting times, patients received induction chemotherapy with cisplatin and 5-fluorouracil followed by either cisplatin concurrent chemoradiotherapy or radiotherapy alone.

Results

Median age was 55 years (range 34-76 years) and 28 (68%) patients were male. 35/41 patients (85%) received 2 or more cycles of induction chemotherapy. Following induction chemotherapy, 32/41 patients (78%) had a clinical response. Concomitant chemotherapy was given to 30/41 (73%). All patients received the planned radiotherapy dose with no delays. There were no treatment related deaths. Six (15%) patients had gastrostomy tubes placed before treatment, and 22 (54%) required nasogastric tube placement during or after treatment for nutritional support. 17 patients required unplanned admissions during treatment for supportive care. At 4 months post treatment assessment 35 out of 41 (85%) patients achieved complete clinical and radiographic response. Median follow-up is 38 months (8-61 months). Local and regional control rate in complete responders at 3 years was 91%. Distant metastases have been found in 4 (9.8%) patients. Three year progression-free survival rate in all patients is 75%. The 3-year cause specific survival and overall survival are 75% and 66% respectively.

Conclusion

Cisplatin-based induction and concurrent chemoradiotherapy provides excellent tumour control with acceptable toxicity for patients with locally advanced tonsillar cancer.
Video-assisted mediastinoscopic transhiatal esophagectomy combined with laparoscopy for esophageal cancer
Authors: Wu Bin , Xue Lei , Qiu Ming , Zheng Xiangmin , Zhong Lei , Qin Xiong , Xu Zhifei
Published: January 2011

Background

Minimally invasive transhiatal esophagectomy for esophageal cancer includes mediastinoscopic and laparoscopic transhiatal esophagectomy. It is inadequate in both two techniques. It is impossible to dissect the lower esophagus with single mediastinoscopy or the upper and middle esophagus with single laparoscopy. We use mediastinoscopy combined with laparoscopy to dissect the whole esophagus and stomach including lymph node dissection. In addition, laparoscopic gastric mobilization leads to less trauma than an open gastroplasty.

Methods

40 cases of video-assisted mediastinoscopic transhiatal esophagectomy were performed and divided into two groups.32 patients were received surgical therapy of single mediastinoscopic esophagectomy with open gastroplasty in group A, while 8 patients were received surgical therapy of mediastinoscopic esophagectomy combined with laparoscopic lower esophageal and gastric dissection in group B. The perioperative complications were recorded.

Results

Video-assisted mediastinoscopic transhiatal esophagectomy was performed successfully both in group A and B. It suggested that mediastinoscopy combined with laparoscopy be better than single mediastinoscopy because of less blood loss, less pain, shorter ICU stay and complete lower mediastinal lymph nodes resection.

Conclusions

Video-assisted mediastinoscopic transhiatal esophagectomy combined with laparoscopy is a safe and minimally invasive technique with whole esophagus and mediastinal lymph node dissection in the clear visualization of the mediastinum, reducing the abdominal trauma.
ER stress response plays an important role in aggregation of α-synuclein
Authors: Jiang Peizhou , Gan Ming , Ebrahim Abdul Shukkur , Lin Wen-Lang , Melrose Heather L , Yen Shu-Hui C
Published: January 2011

Background

Accumulation of filamentous α-synuclein as Lewy bodies is a hallmark of Parkinson's disease. To identify the mechanisms involved in α-synuclein assembly and determine whether the assemblies are cytotoxic, we developed a cell model (3D5) that inducibly expresses wild-type human α-synuclein and forms inclusions that reproduce many morphological and biochemical characteristics of Lewy bodies. In the present study, we evaluated the effects of several histone deacetylase inhibitors on α-synuclein aggregation in 3D5 cells and primary neuronal cultures. These drugs have been demonstrated to protect cells transiently overexpressing α-synuclein from its toxicity.

Results

Contrary to transient transfectants, the drug treatment did not benefit 3D5 cells and primary cultures. The treated were less viable and contained more α-synuclein oligomers, active caspases 3 and 9, as well as ER stress markers than non-treated counterparts. The drug-treated, induced-3D5 cells, or primary cultures from transgenic mice overexpressing (<2 fold) α-synuclein, displayed more α-synuclein oligomers and ER stress markers than non-induced or non-transgenic counterparts. Similar effects were demonstrated in cultures treated with tunicamycin, an ER stressor. These effects were blocked by co-treatment with salubrinal, an ER stress inhibitor. In comparison, co-treatment with a pan caspase inhibitor protected cells from demise but did not reduce α-synuclein oligomer accumulation.

Conclusions

Our results indicate that an increase of wild-type α-synuclein can elicit ER stress response and sensitize cells to further insults. Most importantly, an increase of ER stress response can promote the aggregation of wild type α-synuclein.
Robust dynamic balance of AP-1 transcription factors in a neuronal gene regulatory network
Authors: Miller Gregory M , Ogunnaike Babatunde A , Schwaber James S , Vadigepalli Rajanikanth
Published: January 2011

Background

The octapeptide Angiotensin II is a key hormone that acts via its receptor AT1R in the brainstem to modulate the blood pressure control circuits and thus plays a central role in the cardiac and respiratory homeostasis. This modulation occurs via activation of a complex network of signaling proteins and transcription factors, leading to changes in levels of key genes and proteins. AT1R initiated activity in the nucleus tractus solitarius (NTS), which regulates blood pressure, has been the subject of extensive molecular analysis. But the adaptive network interactions in the NTS response to AT1R, plausibly related to the development of hypertension, are not understood.

Results

We developed and analyzed a mathematical model of AT1R-activated signaling kinases and a downstream gene regulatory network, with structural basis in our transcriptomic data analysis and literature. To our knowledge, our report presents the first computational model of this key regulatory network. Our simulations and analysis reveal a dynamic balance among distinct dimers of the AP-1 family of transcription factors. We investigated the robustness of this behavior to simultaneous perturbations in the network parameters using a novel multivariate approach that integrates global sensitivity analysis with decision-tree methods. Our analysis implicates a subset of Fos and Jun dependent mechanisms, with dynamic sensitivities shifting from Fos-regulating kinase (FRK)-mediated processes to those downstream of c-Jun N-terminal kinase (JNK). Decision-tree analysis indicated that while there may be a large combinatorial functional space feasible for neuronal states and parameters, the network behavior is constrained to a small set of AP-1 response profiles. Many of the paths through the combinatorial parameter space lead to a dynamic balance of AP-1 dimer forms, yielding a robust AP-1 response counteracting the biological variability.

Conclusions

Based on the simulation and analysis results, we demonstrate that a dynamic balance among distinct dimers of the AP-1 family of transcription factors underlies the robust activation of neuronal gene expression in the NTS response to AT1R activation. Such a differential sensitivity to limited set of mechanisms is likely to underlie the stable homeostatic physiological response.
Metabolomic correlation-network modules in Arabidopsis based on a graph-clustering approach
Authors: Fukushima Atsushi , Kusano Miyako , Redestig Henning , Arita Masanori , Saito Kazuki
Published: January 2011

Background

Deciphering the metabolome is essential for a better understanding of the cellular metabolism as a system. Typical metabolomics data show a few but significant correlations among metabolite levels when data sampling is repeated across individuals grown under strictly controlled conditions. Although several studies have assessed topologies in metabolomic correlation networks, it remains unclear whether highly connected metabolites in these networks have specific functions in known tissue- and/or genotype-dependent biochemical pathways.

Results

In our study of metabolite profiles we subjected root tissues to gas chromatography-time-of-flight/mass spectrometry (GC-TOF/MS) and used published information on the aerial parts of 3 Arabidopsis genotypes, Col-0 wild-type, methionine over-accumulation 1 (mto1), and transparent testa4 (tt4) to compare systematically the metabolomic correlations in samples of roots and aerial parts. We then applied graph clustering to the constructed correlation networks to extract densely connected metabolites and evaluated the clusters by biochemical-pathway enrichment analysis. We found that the number of significant correlations varied by tissue and genotype and that the obtained clusters were significantly enriched for metabolites included in biochemical pathways.

Conclusions

We demonstrate that the graph-clustering approach identifies tissue- and/or genotype-dependent metabolomic clusters related to the biochemical pathway. Metabolomic correlations complement information about changes in mean metabolite levels and may help to elucidate the organization of metabolically functional modules.
Bioresponsive matrices in drug delivery
Authors: You Jin-Oh , Almeda Dariela , Ye George JC , Auguste Debra T
Published: January 2011

For years, the field of drug delivery has focused on (1) controlling the release of a therapeutic and (2) targeting the therapeutic to a specific cell type. These research endeavors have concentrated mainly on the development of new degradable polymers and molecule-labeled drug delivery vehicles. Recent interest in biomaterials that respond to their environment have opened new methods to trigger the release of drugs and localize the therapeutic within a particular site. These novel biomaterials, usually termed "smart" or "intelligent", are able to deliver a therapeutic agent based on either environmental cues or a remote stimulus. Stimuli-responsive materials could potentially elicit a therapeutically effective dose without adverse side effects. Polymers responding to different stimuli, such as pH, light, temperature, ultrasound, magnetism, or biomolecules have been investigated as potential drug delivery vehicles. This review describes the most recent advances in "smart" drug delivery systems that respond to one or multiple stimuli.
Clinical application of whole-genome array CGH during prenatal diagnosis: Study of 25 selected pregnancies with abnormal ultrasound findings or apparently balanced structural aberrations
Authors: Evangelidou Paola , Sismani Carolina , Ioannides Marios , Christodoulou Christodoulos , Koumbaris George , Kallikas Ioannis , Georgiou Ioannis , Velissariou Voula , Patsalis Philippos C
Published: January 2011

Background

The purpose of the study was the application and evaluation of array Comparative Genomic Hybridization (array CGH) in selected cases during prenatal diagnosis. Array CGH was applied in 25 fetal samples out of which 15 had normal karyotypes and abnormal ultrasound findings and 10 had apparently balanced structural aberrations with or without abnormal ultrasound findings. DNA was extracted from peripheral blood, chorionic villi samples (CV) and amniotic fluid. Bacterial Artificial Chromosome (BAC) array CGH (Cytochip, BlueGnome Ltd.) of 1 Mb was applied and results were confirmed with either Fluorescence In Situ Hybridization (FISH), Multiplex Ligation-dependant Probe Amplification (MLPA) or Real-Time PCR.

Results

Three out of 25 samples (12%), referred for prenatal array CGH, were found to carry copy number alterations. The number of cases with clinically significant alterations was 2/25 (8%), while one (4%) was of uncertain clinical significance. Two benign Copy Number Variations (CNVs) were also found in 1/25 cases (4%).

Conclusions

The outcome of this study indicates the ability of array CGH to identify chromosomal abnormalities which cannot be detected during routine prenatal cytogenetic analysis, therefore increasing the overall detection rate.
Dynamics of digestive proteolytic system during blood feeding of the hard tick Ixodes ricinus
Authors: Franta Zdeněk , Frantová Helena , Konvičková Jitka , Horn Martin , Sojka Daniel , Mareš Michael , Kopáček Petr
Published: January 2011

Background

Ticks are vectors of a wide variety of pathogens causing severe diseases in humans and domestic animals. Intestinal digestion of the host blood is an essential process of tick physiology and also a limiting factor for pathogen transmission since the tick gut represents the primary site for pathogen infection and proliferation. Using the model tick Ixodes ricinus, the European Lyme disease vector, we have previously demonstrated by genetic and biochemical analyses that host blood is degraded in the tick gut by a network of acidic peptidases of the aspartic and cysteine classes.

Results

This study reveals the digestive machinery of the I. ricinus during the course of blood-feeding on the host. The dynamic profiling of concentrations, activities and mRNA expressions of the major digestive enzymes demonstrates that the de novo synthesis of peptidases triggers the dramatic increase of the hemoglobinolytic activity along the feeding period. Overall hemoglobinolysis, as well as the activity of digestive peptidases are negligible at the early stage of feeding, but increase dramatically towards the end of the slow feeding period, reaching maxima in fully fed ticks. This finding contradicts the established opinion that blood digestion is reduced at the end of engorgement. Furthermore, we show that the digestive proteolysis is localized intracellularly throughout the whole duration of feeding.

Conclusions

Results suggest that the egressing proteolytic system in the early stage of feeding and digestion is a potential target for efficient impairment, most likely by blocking its components via antibodies present in the host blood. Therefore, digestive enzymes are promising candidates for development of novel 'anti-tick' vaccines capable of tick control and even transmission of tick-borne pathogens.
Spatial mapping of gene expression in the salivary glands of the dengue vector mosquito, Aedes aegypti
Authors: Juhn Jennifer , Naeem-Ullah Unsar , Maciel Guedes Bruno Augusto , Majid Asif , Coleman Judy , Paolucci Pimenta Paulo Filemon , Akram Waseem , James Anthony Amade , Marinotti Osvaldo
Published: January 2011

Background

Aedes aegypti mosquitoes are the main vectors of dengue viruses to humans. Understanding their biology and interactions with the pathogen are prerequisites for development of dengue transmission control strategies. Mosquito salivary glands are organs involved directly in pathogen transmission to vertebrate hosts. Information on the spatial distribution of gene expression in these organs is expected to assist in the development of novel disease control strategies, including those that entail the release of transgenic mosquitoes with impaired vector competence.

Results

We report here the hybridization in situ patterns of 30 transcripts expressed in the salivary glands of adult Ae. aegypti females. Distinct spatial accumulation patterns were identified. The products of twelve genes are localized exclusively in the proximal-lateral lobes. Among these, three accumulate preferentially in the most anterior portion of the proximal-lateral lobe. This pattern revealed a salivary gland cell type previously undescribed in Ae. aegypti, which was validated by transmission electron microscopy. Five distinct gene products accumulate in the distal-lateral lobes and another five localize in the medial lobe. Seven transcripts are found in the distal-lateral and medial lobes. The transcriptional product of one gene accumulates in proximal- and distal-lateral lobes. Seven genes analyzed by quantitative PCR are expressed constitutively. The most abundant salivary gland transcripts are those localized within the proximal-lateral lobes, while previous work has shown that the distal-lateral lobes are the most active in protein synthesis. This incongruity suggests a role for translational regulation in mosquito saliva production.

Conclusions

Transgenic mosquitoes with reduced vector competence have been proposed as tools for the control of dengue virus transmission. Expression of anti-dengue effector molecules in the distal-lateral lobes of Ae. aegypti salivary glands has been shown to reduce prevalence and mean intensities of viral infection. We anticipate greater efficiency of viral suppression if effector genes are expressed in all lobes of the salivary glands. Based on our data, a minimum of two promoters is necessary to drive the expression of one or more anti-dengue genes in all cells of the female salivary glands.
The physiological roles of vesicular GABA transporter during embryonic development: a study using knockout mice
Authors: Saito Kenzi , Kakizaki Toshikazu , Hayashi Ryotaro , Nishimaru Hiroshi , Furukawa Tomonori , Nakazato Yoichi , Takamori Shigeo , Ebihara Satoe , Uematsu Masakazu , Mishina Masayoshi , Miyazaki Jun-ichi , Yokoyama Minesuke , Konishi Shiro , Inoue Koichi , Fukuda Atsuo , Fukumoto Manabu , Nakamura Kenji , Obata Kunihiko , Yanagawa Yuchio
Published: January 2011

Background

The vesicular GABA transporter (VGAT) loads GABA and glycine from the neuronal cytoplasm into synaptic vesicles. To address functional importance of VGAT during embryonic development, we generated global VGAT knockout mice and analyzed them.

Results

VGAT knockouts at embryonic day (E) 18.5 exhibited substantial increases in overall GABA and glycine, but not glutamate, contents in the forebrain. Electrophysiological recordings from E17.5-18.5 spinal cord motoneurons demonstrated that VGAT knockouts presented no spontaneous inhibitory postsynaptic currents mediated by GABA and glycine. Histological examination of E18.5 knockout fetuses revealed reductions in the trapezius muscle, hepatic congestion and little alveolar spaces in the lung, indicating that the development of skeletal muscle, liver and lung in these mice was severely affected.

Conclusion

VGAT is fundamental for the GABA- and/or glycine-mediated transmission that supports embryonic development. VGAT knockout mice will be useful for further investigating the roles of VGAT in normal physiology and pathophysiologic processes.
Reactivating aberrantly hypermethylated p15 gene in leukemic T cells by a phenylhexyl isothiocyanate mediated inter-active mechanism on DNA and chromatin
Authors: Jiang Shaohong , Ma Xudong , Huang Yiqun , Xu Yunlu , Zheng Ruiji , Chiao Jen-Wei
Published: January 2011

Background

We have previously demonstrated that phenylhexyl isothiocyanate (PHI), a synthetic isothiocyanate, inhibits histone deacetylases and remodels chromatins to induce growth arrest in HL-60 myeloid leukemia cells in a concentration-dependent manner.

Methods

To investigate the effect of PHI, a novel histone deacetylases inhibitor (HDACi), on demethylation and activation of transcription ofp15in acute lymphoid leukemia cell line Molt-4, and to further decipher the potential mechanism of demethylation, DNA sequencing and modified methylation specific PCR (MSP) were used to screenp15-M andp15-U mRNA after Molt-4 cells were treated with PHI, 5-Aza and TSA. DNA methyltransferase 1 (DNMT1), 3A (DNMT3A), 3B (DNMT3B) andp15mRNA were measured by RT-PCR. P15 protein, acetylated histone H3 and histone H4 were detected by Western Blot.

Results

The genep15in Molt-4 cells was hypermethylated and inactive. Hypermethylation of genep15was attenuated andp15gene was activated de novo after 5 days exposure to PHI in a concentration-dependent manner. DNMT1 and DNMT3B were inhibited by PHI (P < 0.05). Alteration of DNMT3A was not significant at those concentrations. Acetylated histone H3 and histone H4 were accumulated markedly after exposure to PHI.

Conclusion

PHI could induce both DNA demethylation and acetylated H3 and H4 accumulation in Molt-4 cells. Hypermethylation of genep15was reversed andp15transcription could be reactivated de novo by PHI.
8-oxo-7,8-dihydro-2'-deoxyguanosine as a biomarker of oxidative damage in oesophageal cancer patients: lack of association with antioxidant vitamins and polymorphism of hOGG1 and GST
Authors: Lagadu Stéphanie , Lechevrel Mathilde , Sichel François , Breton Jean , Pottier Didier , Couderc Rémy , Moussa Fathi , Prevost Virginie
Published: January 2011

Background

The present report was designed to investigate the origins of elevated oxidative stress measured in cancer patients in our previous work related to a case-control study (17 cases, 43 controls) on oesophageal cancers. The aim was to characterize the relationship between the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), antioxidant vitamins and genetic susceptibility.

Methods

8-oxodG was analysed in peripheral blood mononuclear cells (PBMCs) by High Performance Liquid Chromatography with Electrochemical Detection (HPLC-ED). Analysis of gene polymorphisms in GSTM1 and GSTT1 was performed by multiplex PCR and in GSTP1 and hOGG1 by a PCR-RFLP method. Reversed-phase HPLC with UV detection at 294 nm was used to measure vitamins A and E in serum from the same blood samples.

Results

We observed that in our combined population (cases and control, n = 60), there was no statistically significant correlation between the levels of 8-oxodG and (i) the serum concentration of antioxidant vitamins, vitamin A (P = 0.290) or vitamin E (P = 0.813), or (ii) the incidence of the Ser 326Cys polymorphic variant (P = 0.637) of the hOGG1 gene. Also, the levels of 8-oxodG were not significantly associated with polymorphisms in metabolite-detoxifying genes, such as GST s, except for the positive correlation with Val/Val GST P1 allele (P < 0.0001).

Conclusions

The weakness of our cohort size notwithstanding, vitamins levels in serum and genetic polymorphisms in the hOGG1 or GST genes do not appear to be important modulators of 8-oxodG levels.
Overexpression of Pim-1 in bladder cancer
Authors: Guo Shengjie , Mao Xiaopeng , Chen Junxing , Huang Bin , Jin Chu , Xu Zhenbo , Qiu Shaopeng
Published: January 2011

Background

Pim-1 is a serine-threonine kinase which promotes early transformation, cell proliferation and cell survival during tumorigenesis. Several studies have demonstrated that Pim-1 kinase play a role in different cancer types, however, the function of Pim-1 in bladder cancer is poorly understood.

Methods

Expression and localization of Pim-1 in human normal and malignant bladder specimens were examined by Immunohistochemistry and Pim-1 staining score was compared with several clinicopathologic parameters. To further demonstrate the biological function of Pim-1 in bladder cancer, its expression was validated in five bladder cancer cell lines by western blot and immunohistochemistry analyses. Subsequent knockdown of Pim-1 was achieved by lentivirus encoding small interfering RNA, and the effect of Pim-1 on bladder cell survival and drug sensitivity were further assessed by colony formation and cell proliferation assays.

Results

When compared with normal epithelium, Pim-1 was overexpressed in bladder cancer epithelium, and the expression level was higher in invasive bladder cancer than Non-invasive bladder cancer specimens. Pim-1 was also detected in all the bladder cancer cell lines examined in our study. Moreover, the knockdown of Pim-1 significantly inhibited bladder cancer cell growth and also sensitized cells to chemotherapeutic drugs in vitro.

Conclusions

Our results in this study suggest that Pim-1 may play a role in bladder cancer initiation and progression. Since Pim-1 is also involved in bladder cancer cell survival and drug resistance, Pim-1 is a potential candidate for targeted therapy in bladder cancer.
Trans-arterial chemo-embolization (TACE), with either lipiodol (traditional TACE) or drug-eluting microspheres (precision TACE, pTACE) in the treatment of hepatocellular carcinoma: efficacy and safety results from a large mono-institutional analysis
Authors: Scartozzi Mario , Baroni Gianluca Svegliati , Faloppi Luca , Paolo Marzia Di Pietro , Pierantoni Chiara , Candelari Roberto , Berardi Rossana , Antognoli Stefania , Mincarelli Cinzia , Risaliti Andrea , Marmorale Cristina , Antico Ettore , Benedetti Antonio , Cascinu Stefano
Published: January 2011

More data about TACE and pTACE seem necessary to better define the global treatment strategy for HCC. Aim of our analysis was to evaluate the role of TACE, either with lipiodol (traditional) or drug-eluting microspheres in terms of response rate (RR), time to progression (TTP), overall survival (OS) and toxicity in HCC.

Patients with HCC undergoing traditional TACE or pTACE (either alone or in combination with other treatment options) were eligible

One hundred and fifty patients were analyzed. In the global patient population median OS was 46 months for lipiodol TACE and 19 months for pTACE (p < 0.0001), TTP was 30 months versus 16 months for patients receiving TACE or pTACE respectively (p = 0.003). These results were confirmed also among the group of patients who received exclusive TACE or pTACE. Neither RR nor toxicity was different between TACE or pTACE.

At multivariate analysis, age, the Okuda stage, type of TACE and number of TACE proved to be independent prognostic factors influencing overall survival.

In our experience, lipiodol TACE showed a better OS and TTP over pTACE, without difference in toxicity profile and RR. Among the staging systems analyzed only the Okuda stage seemed able to reliably predict patients outcome.
Co-expression and impact of prostate specific membrane antigen and prostate specific antigen in prostatic pathologies
Authors: Ben Jemaa Awatef , Bouraoui Yosra , Sallami Sataa , Banasr Ahmed , Rais Nawfel Ben , Ouertani Latifa , Nouira Yassin , Horchani Ali , Oueslati Ridha
Published: January 2011

Background

The present study was undertaken to relate the co-expression of prostate-associated antigens, PSMA and PSA, with the degree of vascularization in normal and pathologic (hyperplasia and cancer) prostate tissues to elucidate their possible role in tumor progression.

Methods

The study was carried out in 6 normal, 44 benign prostatic hyperplastic and 39 cancerous human prostates. Immunohistochemical analysis were performed using the monoclonal antibody CD34 to determine the angiogenic activity, and the monoclonal antibodies 3E6 and ER-PR8 to assess PSMA and PSA expression, respectively.

Results

In our study we found that in normal prostate tissue, PSMA and PSA were equally expressed (3.7 ± 0.18 and 3.07 ± 0.11). A significant difference in their expression was see in hyperplastic and neoplastic prostates tissues (16.14 ± 0.17 and 30.72 ± 0.85, respectively) for PSMA and (34.39 ± 0.53 and 17.85 ± 1.21, respectively) for PSA. Study of prostate tumor profiles showed that the profile (PSA+, PSMA-) expression levels decreased between normal prostate, benign prostatic tissue and primary prostate cancer. In the other hand, the profile (PSA-, PSMA+) expression levels increased from normal to prostate tumor tissues. PSMA overexpression was associated with high intratumoral angiogenesis activity. By contrast, high PSA expression was associated with low angiogenesis activity.

Conclusion

These data suggest that these markers are regulated differentially and the difference in their expression showed a correlation with malignant transformation. With regard to the duality PSMA-PSA, this implies the significance of their investigation together in normal and pathologic prostate tissues.
Dynamics of neuroinflammation in the macrosphere model of arterio-arterial embolic focal ischemia: an approximation to human stroke patterns
Authors: Walberer Maureen , Rueger Maria A , Simard Marie-Lune , Emig Beata , Jander Sebastian , Fink Gereon R , Schroeter Michael
Published: January 2011

Background

Neuroinflammation evolves as a multi-facetted response to focal cerebral ischemia. It involves activation of resident glia cell populations, recruitment of blood-derived leucocytes as well as humoral responses. Among these processes, phagocyte accumulation has been suggested to be a surrogate marker of neuroinflammation. We previously assessed phagocyte accumulation in human stroke by MRI. We hypothesize that phagocyte accumulation in the macrosphere model may resemble the temporal and spatial patterns observed in human stroke.

Methods

In a rat model of permanent focal ischemia by embolisation of TiO2-spheres we assessed key features of post-ischemic neuroinflammation by the means of histology, immunocytochemistry of glial activation and influx of hematogeneous cells, and quantitative PCR of TNF-α, IL-1, IL-18, and iNOS mRNA.

Results

In the boundary zone of the infarct, a transition of ramified microglia into ameboid phagocytic microglia was accompanied by an up-regulation of MHC class II on the cells after 3 days. By day 7, a hypercellular infiltrate consisting of activated microglia and phagocytic cells formed a thick rim around the ischemic infarct core. Interestingly, in the ischemic core microglia could only be observed at day 7. TNF-α was induced rapidly within hours, IL-1β and iNOS peaked within days, and IL-18 later at around 1 week after ischemia.

Conclusions

The macrosphere model closely resembles the characteristical dynamics of postischemic inflammation previously observed in human stroke. We therefore suggest that the macrosphere model is highly appropriate for studying the pathophysiology of stroke in a translational approach from rodent to human.